Method for the prophylaxis and/or treatment of proliferative and /or inflammatory skin disorders

ABSTRACT

The present invention relates generally to a method for the prophylaxis and/or treatment of skin disorders, and in particular proliferative and/or inflammatory skin disorders, and to genetic molecules useful for same. The present invention is particularly directed to genetic molecules capable of modulating growth factor interaction with its receptor on epidermal keratinocytes to inhibit, reduce or otherwise decrease stimulation of this layer of cells. The present invention contemplates, in a most preferred embodiment, a method for the prophylaxis and/or treatment of psoriasis.

This is a continuation of application Ser. No. 08/666,392, now U.S. Pat.No. 5,929,040, filed Jun. 20, 1996 which is a 371 national phase filingof PCT/AU95/00410, filed Jul. 6, 1995.

The present invention relates generally to a method for the prophylaxisand/or treatment of skin disorders, and in particular proliferativeand/or inflammatory skin disorders, and to genetic molecules useful forsame. The present invention is particularly directed to geneticmolecules capable of modulating growth factor interaction with itsreceptor on epidermal keratinocytes to inhibit, reduce or otherwisedecrease stimulation of this layer of cells. The present inventioncontemplates, in a most preferred embodiment, a method for theprophylaxis and/or treatment of psoriasis.

Bibliographic details of the publications numerically referred to inthis specification are collected at the end of the description. SequenceIdentity Numbers (SEQ ID NOs.) for the nucleotide sequences referred toin the specification are defined following the bibliography.

Throughout this specification, unless the context requires otherwise,the word “comprise”, or variations such as “comprises” or “comprising”,will be understood to imply the inclusion of a stated element or integeror group of elements or integers but not the exclusion of any otherelement or integer or group of elements or integers.

Psoriasis and other similar conditions are common and often distressingproliferative and/or inflammatory skin disorders affecting or having thepotential to affect a significant proportion of the population. Thecondition arises from over proliferation of basal keratinocytes in theepidermal layer of the skin associated with inflammation in theunderlying dermis. Whilst a range of treatments have been developed,none is completely effective and free of adverse side effects. Althoughthe underlying cause of psoriasis remains elusive, there is someconsensus of opinion that the condition arises at least in part fromover expression of local growth factors and their interaction with theirreceptors supporting keratinocyte proliferation via keratinocytereceptors which appear to be more abundant during psoriasis.

One important group of growth factors are the dermally-derivedinsulin-like growth factors (IGFs) which support keratinocyteproliferation. In particular, IGF-I and IGF-II are ubiquitous peptideseach with potent mitogenic effects on a broad range of cells. Moleculesof the IGF type are also known as “progression factors” promoting“competent” cells through DNA synthesis. The IGFs act through a commonreceptor known as the Type I or IGF-I receptor, which is tyrosine kinaselinked. They are synthesised in mesenchymal tissues, including thedermis, and act on adjacent cells of mesodermal, endodermal orectodermal origin. The regulation of their synthesis involves growthhormone (GH) in the liver, but is poorly defined in most tissues (1).

Particular proteins, referred to as IGF binding proteins (IGFBPs),appear to be involved in autocrine/paracrine regulation of tissue IGFavailability (2). Six IGFBPs have so far been identified. The exacteffects of the IGFBPs is not clear and observed effects in vitro havebeen inhibitory or stimulatory depending on the experimental methodemployed (3). There is some evidence, however, that certain IGFBPs areinvolved in targeting IGF-I to its cell surface receptor.

Skin, comprising epidermis and underlying dermis, has GH receptors ondermal fiboblasts (4). Fibroblasts synthesize IGF-I as well as IGFBPs-3,-4, -5 and -6 (5) which may be involved in targeting IGF-I to adjacentcells as well as to the overlaying epidermis. The major epidermal celltype, the keratinocyte, does not synthesize IGF-I, but possesses IGF-Ireceptors and is responsive to IGF-I (6).

It is apparent, therefore, that IGF-I and other growth promotingmolecules, are responsible for or at least participate in a range ofskin cell activities. In accordance with the present invention, theinventors have established that abberations in the normal functioning ofthese molecules or abberations in their interaction with their receptorsis an important factor in proliferative and/or inflammatory skindisorders. It is proposed, therefore, to target these molecules or othermolecules which facilitate their functioning or interaction with theirreceptors to thereby ameliorate the effects of abberant activity duringor leading to skin disease conditions.

Accordingly, one aspect of the present invention contemplates a methodfor ameliorating the effects of a proliferative and/or inflammatory skindisorder in a mammal, said method comprising contacting theproliferating and/or inflamed skin or skin capable of proliferationand/or inflammation with an effective amount of a nucleic acid moleculeor chemical analogue thereof capable of inhibiting or otherwise reducinga growth factor mediated cell proliferation and/or inflammation.

Growth factor mediated cell proliferation and inflammation are alsoreferred to as epidermal hyperplasias and may be mediated by any numberof molecules such as but not limited to IGF-I, keratinocyte growthfactor (KGF), transforming growth factor-α (TGFα), tumour necrosisfactor-α (TNFα), interleukin-1, -4, -6 and 8 (IL-1, IL-4, IL-6 and IL-8,respectively), basic fibroblast growth factor (bFGF) or a combination ofone or more of the above. The present invention is particularlydescribed and exemplified with reference to IGF-I and its receptor(IGF-I receptor) and to IGF-I facilitating molecules, IGFBPs, sincetargeting these molecules according to the methods contemplated hereinprovides the best results to date. This is done, however, with theunderstanding that the present invention extends to any growth factor orcytokine-like molecule, a receptor thereof or a facilitating moleculelike the IGFBPs involved in skin cell proliferation such as thosemolecules contemplated above and/or their receptors and/or facilitatingmolecules therefor.

According to this preferred embodiment, there is provided a method forameliorating the effects of a proliferative and/or inflammatory skindisorder in a mammal, said method comprising contacting theproliferating and/or inflamed skin or skin capable of proliferationand/or inflammation with an effective amount of a nucleic acid moleculeor chemical analogue thereof capable of inhibiting or otherwise reducingIGF-I mediated cell proliferation and/or inflammation.

The present invention is particularly described by psoriasis as theproliferative skin disorder. However, the subject invention extends to arange of proliferative and/or inflammatory skin disorders or epidermalhyperplasias such as but not limited to psoriasis, ichthyosis,pityriasis rubra pilaris (“PRP”), seborrhoea, keloids, keratoses,neoplasias and scleroderma, warts, benign growths and cancers of theskin.

In a preferred embodiment, therefore, the present invention is directedto a method for ameliorating the effects of psoriasis, said methodcomprising contacting proliferating skin or skin capable ofproliferation with an effective amount of a nucleic acid molecule orchemical analogue thereof capable of inhibiting or otherwise reducingIGF-I mediated cell proliferation.

The present invention extends to any mammal such as but not limited tohumans, livestock animals (e.g. horses, sheep, cows, goats, pigs,donkeys), laboratory test animals (e.g. rabbits, mice, guinea pigs),companion animals (e.g. cats, dogs) and captive wild animals. However,the instant invention is particularly directed to proliferative and/orinflammatory skin disorders such as psoriasis in humans.

The aspects of the subject invention instantly contemplated areparticularly directed to the topical application of one or more suitablenucleic molecules capable of inhibiting, reducing or otherwiseinterfering with IGF-mediated cell proliferation and/or inflammation.More particularly, the nucleic acid molecule targets IGF-I interactionwith its receptor. Conveniently, therefore, the nucleic acid molecule isan antagonist of IGF-I interaction with its receptor. Most conveniently,the nucleic acid molecule antagonist is an antisense molecule to theIGF-I receptor, to IGF-I itself or to a molecule capable of facilitatingIGF-I interaction with its receptor such as but not limited to an IGFBP.

Insofar as the invention relates to IGFBPs, the preferred molecules areIGFBP-2, -3, 4, -5 and -6. The most preferred molecules are IGFBP-2 andIGFBP-3.

The nucleotide sequences of IGFBP-2 and IGFBP-3 are set forth in FIGS.1A and 1B (SEQ ID NO. 1) and 2A and 2B (SEQ ID NO. 2), respectively.According to a particularly preferred aspect of the present invention,there is provided a nucleic acid molecule comprising at least about tennucleotides capable of hybridising to, forming a heterodouplex orotherwise interacting with an mRNA molecule directed from a genecorresponding to a genomic form of SEQ ID NO. 1 and/or SEQ ID NO. 2 andwhich thereby reduces or inhibits translation of said mRNA molecule.Preferably, the nucleic acid molecule is at least about 15 nucleotidesin length and more preferably at least about 20-25 nucleotides inlength. However, the instant invention extends to any length nucleicacid molecule including a molecule of 100-200 nucleotides in length tocorrespond to the full length of or near full length of the subjectgenes.

The nucleotide sequence of the antisense molecules may correspondexactly to a region or portion of SEQ ID NO. 1 or SEQ ID NO. 2 or maydiffer by one or more nucleotide substitutions, deletions and/oradditions. It is a requirement, however, that the nucleic acid moleculeinteract with an mRNA molecule to thereby reduce its translation intoactive protein.

Examples of potential antisense molecules for IGFBP-2 and IGFBP-3 arethose capable of interacting with sequences selected from the lists inExamples 6 and 7, respectively.

The nucleic acid molecules in the form of an antisense molecule may belinear or covalently closed circular and single stranded or partiallydouble stranded. A double stranded molecule may form a triplex withtarget mRNA or a target gene. The molecule may also be protected from,for example, nucleases, by any number of means such as using a nonionicbackbone or a phosphorothioate linkage. A convenient nonionic backbonecontemplated herein is ethylphosphotriester linkage or a2′-O-methylribosyl derivative.

Examples of suitable oligonucleotide analogues are convenientlydescribed in Ts'O et al (7).

Alternatively, the antisense molecules of the present invention maytarget the IGF-I gene itself or its receptor or a multivalent antisensemolecule may be constructed or separate molecules administered whichtarget at least two or an IGFBP, IGF-I and/or IGF-I-receptor. Examplesof suitable antisense molecules capable of targetting the IGF-I receptorare those capable of interacting with sequences selected from the listin Example 8. One particularly useful antisense molecule is5′-ATCTCTCCGCTTCCTTTC-3′ (SEQ ID NO. 10). A particularly preferredembodiment of the present invention contemplates a method ofameliorating the effects of psoriasis, said method comprising contactingproliferating skin or skin capable of proliferation with an effectiveamount of one or more nucleic acid molecules or chemical analoguesthereof capable of inhibiting or otherwise reducing IGF-I mediated cellproliferation wherein said one or more molecules comprises apolynucleotide capable of interacting with mRNA directed from two ormore of an IGF-I gene, an IGF-I receptor gene or a gene encoding anIGFBP such as IGFBP-2 and/or IGFBP-3.

In accordance with one aspect of the present invention the nucleic acidmolecule is topically applied in aqueous solution or in conjunction witha cream, ointment, oil or other suitable carrier and/or diluent. Asingle application may be sufficient depending on the severity orexigencies of the condition although more commonly, multipleapplications are required ranging from hourly, multi-hourly, daily,multi-daily, weekly or monthly, or in some other suitable time interval.The treatment might comprise solely the application of the nucleic acidmolecule or this may be applied in conjunction with other treatments forthe skin proliferation and/or inflammatory disorder being treated or forother associated conditions including microbial infection, bleeding andthe formation of a variety of rashes.

As an alternative to or in conjunction with antisense therapy, thesubject invention extends to the nucleic acid molecule as, orincorporating, a ribozyme including a minizyme to, for example, IGF-I,its receptor or to molecules such as IGFBPs and in particular IGFBP-2and -3. Ribozymes are synthetic nucleic acid molecules which possesshighly specific endoribonuclease activity. In particular, they comprisea hybridising region which is complementary in nucleotide sequence to atleast part of a target RNA. Ribozymes are well described by Haseloff andGerlach (8) and in International Patent Application No. WO 89/05852. Thepresent invention extends to ribozymes which target mRNA specified bygenes encoding IGF-I, its receptor or one or more IGFBPs such as IGFBP-2and/or IGFBP-3.

According to this embodiment, there is provided in a particularlypreferred aspect a ribozyme comprising a hybridising region and acatalytic region wherein the hybridising region is capable ofhybridising to at least part of a target mRNA sequence transcribed froma genomic gene corresponding to SEQ ID NO. 1 or SEQ ID NO. 2 whereinsaid catalytic domain is capable of cleaving said target mRNA sequenceto reduce or inhibit IGF-I mediated cell proliferation and/orinflammation.

Yet another aspect of the present invention contemplates co-suppressionto reduce expression or to inhibit translation of an endogenous geneencoding, for example, IGF-I, its receptor, or IGFBPs such as IGFBP-2and/or -3. In co-suppression, a second copy of an endogenous gene or asubstantially similar copy or analogue of an endogenous gene isintroduced into a cell following topical administration. As withantisense molecules, nucleic acid molecules defining a ribozyme ornucleic acid molecules useful in co-suppression may first be protectedsuch as by using a nonionic backbone.

The efficacy of the nucleic acid molecules of the present invention canbe conveniently tested and screened using an in vitro system comprisinga basal keratinocyte cell line. A particularly useful system comprisesthe HaCaT cell line described by Boukamp et al (9). In one assay, IGF-Iis added to an oligonucleotide treated HaCaT cell line. Alternatively,growth of oligonucleotide treated HaCaT cells is observed on a feederlayer of irradiated 3T3 fibroblasts. Using such in vitro assays, it isobserved that antisense oligonucleotides to IGFBP-3, for example,inhibit production of IGFBP-3 by HaCaT cells. Other suitable animalmodels include the nude mouse/human skin graft model (15; 16) and the“flaky skin” mouse model (17; 18). In the nude mouse model,microdermatome biopsies of psoriasis lesions are taken under localanaesthetic from volunteers then transplanted to congenital athymic(nude) mice. These transplanted human skin grafts maintain thecharacteristic hyperproliferating epidermis for 6-8 weeks. They are anestablished model for testing the efficacy of topically appliedtherapies for psoriasis. In the “flaky skin” mouse model, the fsn/fsnmutation produces mice with skin resembling human psoriasis. This mouse,or another mutant mouse with a similar phenotype is a further in vivomodel to test the efficacy of topically applied therapies for psoriasis.

Another aspect of the present invention contemplates a pharmaceuticalcomposition for topical administration which comprises a nucleic acidmolecule capable of inhibiting or otherwise reducing IGF-I mediated cellproliferation such as psoriasis and one or more pharmaceuticallyacceptable carriers and/or diluents. Preferably, the nucleic acidmolecule is an antisense molecule to IGF-I, the IGF-I receptor or anIGFBP such as IGFBP-2 and/or IGFBP-3 or comprises a ribozyme to one ormore of these targets or is a molecule suitable for co-suppression ofone or more of these targets. The composition may comprise a singlespecies of a nuleic acid molecule capable of targeting one of IGF-I, itsreceptor or an IGFBP, such as IGFBP-2 or IGFBP-3 or may be amulti-valent molecule capable of targeting two or more of IGF-I, itsreceptor or an IGFBP, such as IGFBP-2 and/or IGFBP-3.

The nucleic acid molecules may be administered in dispersions preparedin creams, ointments, oil or other suitable carrier and/or diluent suchas glycerol, liquid polyethylene glycols and/or mixtures thereof. Underordinary conditions of storage and use, these preparations may contain apreservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for topical use include sterileaqueous solutions (where water soluble) or dispersions and powders forthe extemporaneous preparation of topical solutions or dispersion. Inall cases, the form is preferably sterile although this is not anabsolute requirement and is stable under the conditions of manufactureand storage. The carrier can be a solvent or dispersion mediumcontaining, for example, water, ethanol, polyol (for example, glycerol,propylene glycol, and liquid polyethylene glycol, and the like),suitable mixtures thereof and vegetable oils. The proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case of dispersionand by the use of superfactants. The prevention of the action ofmicroorganism can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thirmerosal and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars or sodium chloride.

Topical solutions are prepared by incorporating the nucleic acidmolecule compound in he required amount in the appropriate solvent withvarious of the other ingredients numerated above, as required, followedby where necessary filter sterilization.

As used herein “pharmaceutically acceptable carriers and/or diluents”include any and all solvents, dispersion media, aqueous solutions,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents, and the like. The use of such media and agents forpharmaceutical active substances is well known in the art. Exceptinsofar as any conventional media or agent is incomparable with theactive ingredient, use thereof in the pharmaceutical compositions iscontemplated. Supplementary active ingredients can also be incorporatedinto the compositions. Conveniently, the nucleic acid molecules of thepresent invention are stored in freeze-dried form and are reconstitutedprior to use.

Yet another aspect of the present invention contemplates the use of anucleic acid molecule in the manufacture of a medicament for thetreatment of proliferative and/or inflammatory skin disorders mediatedby a growth factor. The proliferative and/or inflammatory skin disorderis generally psoriasis and the nucleic acid molecule targets IGF-I, theIGF-I receptor and/or an IGFBP such as IGFBP-2 and/or IGFBP-3.

Still a further aspect of the present invention contemplates an agentcomprising a nucleic acid molecule as hereinbefore defined useful in thetreatment of proliferative and/or inflammatory skin disorders, such aspsoriasis.

The present invention is further described by the following non-limitingFigures and/or Examples.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B are a representation of the nucleotide sequence ofIGFBP-2 (Seq Id No: 1).

FIGS. 2A and 2D are a representation of the nucleotide sequence ofIGFBP-3 (Seq. Id. No: 2).

FIGS. 3A—3G are a representation of the nucleotide sequence ofIGF-1-receptor (Seq. Id. No: 3).

FIG. 4A is a photographic representation of a Western ligand blot ofHaCaT conditioned medium showing IGFBP-3 secreted in 24 hours after 7day treatment with phosphorothioate oligonucleotides (BP3AS2, BP3AS3 andBP3S) at 0.5 μM and 5 μM; * no oligonucleotide added.

FIG. 4B is a graphical representation of a scanning imaging desitometryof Western ligand blot (FIG. 4A), showing relative band intensities ofIGFBP-3 and the 24 kDa IGFBP-4 after treatment with phosphorothioateoligonucleotides; * no oligonucleotide added.

FIG. 5A is a photographic representation of a Western ligand blot ofHaCaT conditioned medium showing IGFBP-3 secreted in 24 hours after 7day treatment with phosophorothioate oligonucleotide BP3AS2 at 0.5 μMcompared with several control oligonucleotides at 0.5 μM. (a)oligonucleotide BP3AS2NS; (b) oligonucleotide BP3AS4; (c)oligonucleotide BP3AS4NS; and (untreated), no oligonucleotide added.

FIG. 5B is a graphical representation of a scanning imaging densitometryof Western ligand blot (FIG. 5A), showing relative band intensities ofIGFBP-3 after treatment with phosphorothioate oligonucleotides as inFIG. 5A, showing IGFBP-3 band intensities expressed as a percentage ofthe average band intensity from conditioned, medium of cells not treatedwith oligonucleotide.

FIG. 6 is a graphical representation showing inhibition of IGF-I bindingby antisense oligonucleotides to IGF-I receptor. IGFR.AS: antisense;IGFR.S: sense.

FIG. 7 is a graphical representation showing inhibition of IGFBP-3production in culture medium following initial treatment with antisenseoligonucleotides once daily over a 2 day period.

FIG. 8 is a graphical representation showing optimization of IGFBP-3antisense oligonucleotide concentration as determined by relativeIGFBP-3 concentration in culture medium.

EXAMPLE 1 In Vitro Assay: Cells

The differentiated human keratinocyte cell line, HaCaT (9) was used inthe in vitro assay. Cells at passage numbers 33 to 36 were maintained asmonolayer cultures in 5% v/v CO₂ at 37° C. in Keratinocyte-SFM (Gibco)containing EGF and bovine pituitary extract as supplied. Mediacontaining foetal calf serum were avoided because of the high content ofIGF-I binding proteins in serum.

Feeder layer plates of lethally irradiated 3T3 fibroblasts were preparedexactly as described by Rheinwald and Green (10).

EXAMPLE 2 In Vitro Assay: Thymidine Incorporation Assay

Cells were grown to 4 days post confluence in 2 cm² wells with dailymedium changes of Keratinocyte-SFM, then the medium was changed to DMEM(Cytosystems, Australia), with the following additions: 25 mM Hepes,0.19% w/v, sodium bicarbonate, 0.03% w/v glutamine (Sigma Chemical Co,USA), 50 IU/ml penicillin and 50 μg/ml streptomycin (Flow Laboratories).After 24 hours, IGF-I or tIGF-I was added to triplicate wells, at theconcentrations indicated, in 0.5 ml fresh DMEM containing 0.02% v/vbovine serum albumin (Sigma molecular biology grade) and incubated for afurther 21 hours. [³H]-Thymidine (0.1 μCi/well) was then added and thecells incubated for a further 3 hours. The medium was then aspirated andthe cells washed once with ice-cold PBS and twice with ice-cold 10% v/vTCA. The TCA-precipitated monolayers were then solubilized with 0.25MNaOH (200 μl/well), transferred to scintillation vials and radioactivitydetermined by liquid scintillation counting (Pharmacia Wallac 1410liquid scintillation counter).

EXAMPLE 3 Western Ligand Blotting

HaCaT conditioned medium (250 μl) was concentrated by adding 750 μl coldethanol, incubating at −20° C. for 2 hours and centrifuging at 16,000 gfor 20 min at 4° C. The resulting pellet was air dried, resuspendedthoroughly in non-reducing Laemmli sample buffer, heated to 90° C. for 5minutes and separated on 12% w/v SDS-PAGE according to the method ofLaemmli (1970). Separated proteins were electrophoretically transferredto nitrocellulose membrane (0.45 mm, Schleicher and Schuell, Dassel,Germany) in a buffer containing 25 mM Tris, 192 mM glycine and 20% v/vmethanol. IGFBPs were then visualised by the procedure of Hossenlopp etal (11), using [¹²⁵I]-IGF-I, followed by autoradiography.Autoradiographs were scanned in a BioRad Model GS-670 ImagingDensitometer and band densities were determined using the MolecularAnalyst program.

EXAMPLE 4 Antisense Oligonucleotides

Phosphorothioate oligodeoxynucleotides were synthesised by Bresatec,Adelaide, South Australia, Australia. The following antisense sequenceswere used: BP3AS2, 5′-GCG CCC GCT GCA TGA CGC CTG CAA C-3′ (SEQ ID NO.4), a 25 mer complementary to the start codon region of the humanIGFBP-3 mRNA; BP3AS3, 5′-CGG GCG GCT CAC CTG GAG CTG GCG-3′ (SEQ ID NO.5), a 24 mer complementary to the exon 1/intron 1 splice site; BP3AS4,5′-AGG CGG CTG ACG GCA CTA-3′ (SEQ ID NO. 6), an 18 mer complementary toa region of the coding sequence lacking RNA secondary structure andoligonucleotide-dimer formation (using the computer software “OLIGO forPC”). Since BP3AS4 was found to be ineffective at inhibiting IGFBP-3synthesis, it was used as a control. The following additional controloligonucleotide sequences were used: BP3S, 5′-CAG GCG TCA TGC AGC GGGC-3′ (SEQ ID NO. 7), an 18 mer sense control sequence equivalent to thestart codon region; BP3AS2NS, 5′-CGG AGA TGC CGC ATG CCA GCG CAG G-3′(SEQ ID NO. 8), a 25 mer randomised sequence with the same GC content asBP3AS2; BP3AS4NS, 5′-GAC AGC GTC GGA GCG ATC-3′ (SEQ ID NO. 9), an 18mer randomised sequence with the same GC content as BP3AS4NS. Design ofthe oligonucleotides was based on the human IGFBP-3 cDNA sequence ofSpratt et al (12).

Cells were grown to one day post confluence in 2 cm² wells with dailymedium changes of 0.5 ml Keratinocyte-SFM, then subjected to dailymedium changes of Keratinocyte-SFM for a further 4 days. Daily additionsof 0.5 ml fresh Keratinocyte-SFM were then continued for a further 7days, except that at the time of medium addition, 5 μl oligonucleotidein PBS was added to give the final concentrations indicated, then thewells were shaken to mix the oligonucleotide. After the final addition,cells were incubated for 24 hours and the medium collected for assay ofIGFBPs. Cells were then counted after trypsinisation in a CoulterIndustrial D Counter, Coulter Bedfordshire, UK. Cell numbers afteroligonucleotide treatment differed by less than 10%.

EXAMPLE 5 Antisense Oligonucleotides Inhibit IGFBP-3 Synthesis

HaCaT cells secrete mainly IGFBP-3 (>95%), with the only other IGFBPdetectable in HaCaT conditioned medium being IGFBP4 (<5%). The effect onIGFBP-3 and IGFBP-4 synthesis of antisense oligonucleotides at twoconcentrations, 5 μM and 0.5 μM, was tested. Two oligonucleotides wereused, BP3AS2 and BP3AS3, directed against the start site and the intron1/exon 1 splice site, respectively of the IGFBP-3 mRNA. As a control, asense oligonucleotide corresponding to the start site was used. As shownin FIGS. 4A and 4B, all oligonucleotides at 5 μM caused a significantreduction of IGFBP-3 synthesis compared with untreated cells, however,the two antisense oligonucleotides inhibited IGFBP-3 synthesis ofapproximately 50% compared to the sense control (FIG. 4B). The antisenseoligonucleotide directed to the start codon appeared to be moreeffective of the two, the difference being more apparent at the lowerconcentration of 0.5 μM. The cells of IGFBP-4 secreted by the HaCaTcells make photographic reproduction of the bands on Western ligandblots difficult, however densitometry measurements provide adequaterelative quantitation. This resulted in the significant observation hatIGFBP-4 levels were unaffected by oligonucleotide addition to the cells,suggesting that the observed inhibitory effects on IGFBP-3 are specific.

To further investigate the inhibitory effects of the more effective ofthe two antisense oligonucleotides, BP3AS2, inhibition by thisoligonucleotide at 0.5 μM was compared with a number of controloligonucleotides, including one antisense oligonucleotide to IGFBP-3that had proved to be ineffective at 0.5 μM. As shown in FIGS. 5A and5B, BP3AS2 was again inhibitory, resulting in levels of IGFBP-3 ofapproximately 50% of the most non-specifically inhibitory controloligonucleotide, the randomised equivalent of BP3AS2. The other controloligonucleotides caused no reduction in IGFBP-3 levels at 0.5 μM,compared to untreated cells. Of possible significance is the fact thatthis control oligonucleotide, BP3AS2NS, like BP3AS2 itself, has thehighest potential T_(m) of the three control oligonucleotides used inthis experiment, enhancing the probability of non-specific base pairingwith non-target mRNAs. However, the lack of inhibition of IGFBP-4secretion by BP3AS2 suggests that this oligonucleotide is selective evencompared with the most closely related protein likely to be present inthis cell line.

EXAMPLE 6 Antisense Oligonucleotides of IGFBP2

Antisense oligonucleotides to IGFBP2 may be selected from moleculescapable of interacting with one or more oligonucleotides selected fromoligonucleotides having the sequence of nucleotides 1-15, 2-16, 3-17,4-18, 5-19, 6-20, 7-21, 8-22, 9-23, 10-24, 11-25, 12-26, 13-27, 14-28,15-29, 16-30, 17-31, 18-32, 19-33, 20-34, 21-35, 22-36, 23-37, 24-38,25-39, 26-40, 27-41, 28-42, 29-43, 30-44, 31-45, 32-46, 33-47, 34-48,35-49, 36-50, 37-51, 38-52, 39-53, 40-54, 41-55, 42-56, 43-57, 44-58,45-59, 46-60, 47-61, 48-62, 49-63, 50-64, 51-65, 52-66, 53-67, 54-68,55-69, 56-70, 57-71, 58-72, 59-73, 60-74, 61-75, 62-76, 63-77, 64-78,65-79, 66-80, 67-81, 68-82, 69-83, 70-84, 71-85, 72-86, 73-87, 74-88,75-89, 76-90, 77-91, 78-92, 79-93, 80-94, 81-95, 82-96, 83-97, 84-98,85-99, 86-100, 87-101, 88-102, 89-103, 90-104, 91-105, 92-106, 93-107,94-108, 95-109, 96-110, 97-111, 98-112, 99-113, 100-114, 101-115,102-116, 103-117, 104-118, 105-119, 106-120, 107-121, 108-122, 109-123,110-124; 111-125, 112-126, 113-127, 114-128, 115-129, 116-130, 117-131,118-132, 119-133, 120-134, 121-135, 122-136, 123-137, 124-138, 125-139,126-140, 127-141, 128-142, 129-143, 130-144, 131-145, 132-146, 133-147,134-148, 135-149, 136-150, 137-151, 138-152, 139-153, 140-154, 141-155,142-156, 143-157, 144-158, 145-159, 146-160, 147-161, 148-162, 149-163,150-164, 151-165, 152-166, 153-167, 154-168, 155-169, 156-170, 157-171,158-172, 159-173, 160-174, 161-175, 162-176, 163-177, 164-178, 165-179,166-180, 167-181, 168-182, 169-183, 170-184, 171-185, 172-186, 173-187,174-188, 175-189, 176-190, 177-191, 178-192, 179-193, 180-194, 181-195,182-196, 183-197, 184-198, 185-199, 186-200, 187-201, 188-202, 189-203,190-204, 191-205, 192-206, 193-207, 194-208, 195-209, 196-210, 197-211,198-212, 199-213, 200-214, 201-215, 202-216, 203-217, 204-218, 205-219,206-220, 207-221, 208-222, 209-223, 210-224, 211-225, 212-226, 213-227,214-228, 215-229, 216-230, 217-231, 218-232, 219-233, 220-234, 221-235,222-236, 223-237, 224-238, 225-239, 226-240, 227-241, 228-242, 229-243,230-244, 231-245, 232-246, 233-247, 234-248, 235-249, 236-250,237-251,238-252, 239-253, 240-254, 241-255, 242-256, 243-257, 244-258, 245-259,246-260, 247-261, 248-262, 249-263, 250-264, 251-265, 252-266, 253-267,254-268, 255-269, 256-270, 257-271, 258-272, 259-273, 260-274, 261-275,262-276, 263-277, 264-278, 265-279, 266-280, 267-281, 268-282, 269-283,270-284, 271-285, 272-286, 273-287, 274-288, 275-289, 276-290, 277-291,278-292, 279-293, 280-294, 281-295, 282-296, 283-297, 284-298, 285-299,286-300, 287-301, 288-302, 289-303, 290-304, 291-305, 292-306, 293-307,294-308, 295-309, 296-310, 297-311, 298-312, 299-313, 300-314, 301-315,302-315, 303-317, 304-318, 305-319, 306-320, 307-321, 308-322, 309-323,310-324, 311-325, 312-326, 313-327, 314-328, 315-329, 316-330, 317-331,318-332, 319-333, 320-334, 321-335, 322-336, 323-337, 324-338, 325-339,326-340, 327-341, 328-342, 329-343, 330-344, 331-345, 332-346, 333-347,334-348, 335-349, 336-350, 337-351, 338-352, 339-353, 340-354, 341-355,342-356, 343-357, 344-358, 345-359, 346-360, 347-361, 348-362, 349-363,350-364, 351-365, 352-366, 353-367, 354-368, 355-369, 356-370, 357-371,358-372, 359-373, 360-374, 361-375, 362-376, 363-377, 364-378, 365-379,366-380, 367-381, 368-382, 369-383, 370-384, 371-385, 372-386, 373-387,374-388, 375-389, 376-390, 377-391, 378-392, 379-393, 380-394, 381-395,382-396, 383-397, 384-398, 385-399, 386-400, 387-401, 388-402, 389-403,390-404, 391-405, 392-406, 393-407, 394-408, 395-409, 396-410, 397-411,398-412, 399-413, 400-414, 401-415, 402-416, 403-417, 404-418, 405-419,406-420, 407-421, 408-422, 409-423, 410-424, 411-425, 412-426, 413-427,414-428, 415-429, 416-430, 417-431, 418-432, 419-433, 420-434, 421-435,422-436, 423-437, 424-438, 425-439, 426-440, 427-441, 428-442, 429-443,430-444, 431-445, 432-446, 433-447, 434-448, 435-449, 436-450, 437-451,438-452, 439-453, 440-454, 441-455, 442-456, 443-457, 444-458, 445-459,446-460, 447-461, 448-462, 449-463, 450-464, 451-465, 452-466, 453-467,454-468, 455-469, 456-470, 457-471, 458-472, 459-473, 460-474, 461-475,462-476, 463-477, 464-478, 465-479, 466-480, 467-481, 468-482, 469-483,470-484, 471-485, 472-486, 473-487, 474-488, 475-489, 476-490, 477-491,478-492, 479-493, 480-494, 481-495, 482-496, 483-497, 484-498, 485-499,486-500, 487-501, 488-502, 489-503, 490-504, 491-505, 492-506, 493-507,494-508, 495-509, 496-510, 497-511, 498-513, 499-514, 500-515, 501-515,502-516, 503-517, 504-518, 505-519, 506-520, 507-521, 508-522, 509-523,510-524, 511-525, 512-526, 513-527, 514-528, 515-529, 516-530, 517-531,518-532, 519-533, 520-534, 521-535, 522-536, 523-537, 524-538, 525-539,526-540, 527-541, 528-542, 529-543, 530-544, 531-545, 532-546, 533-547,534-548, 535-549, 536-550, 537-551, 538-552, 539-553, 540-554, 541-555,542-556, 543-557, 544-558, 545-559, 546-560, 547-561, 548-562, 549-563,550-564, 551-565, 552-566, 553-567, 554-568, 555-569, 556-570, 557-571,558-572, 559-573, 560-574, 561-575, 562-576, 563-577, 564-578, 565-579,566-580, 567-581, 568-582, 569-583, 570-584, 571-585, 572-586, 573-587,574-588, 575-589, 576-590, 577-591, 578-592, 579-593, 580-594, 581-595,582-596, 583-597, 584-598, 585-599, 586-600, 587-601, 588-602, 589-603,590-604, 591-605, 592-006, 593-607, 594-608, 595-609, 596-610, 597-611,598-612, 599-613, 600-614, 601-615, 602-616, 603-617, 604-618, 605-619,606-620, 607-621, 608-622, 609-623, 610-624, 611-625, 612-626, 613-627,614-628, 615-629, 616-630, 617-631, 618-632, 619-633, 620-634, 621-635,622-636, 623-637, 624-638, 625-639, 626-640, 627-641, 628-642, 629-643,630-644, 631-645, 632-646, 633-647, 634-648, 635-649, 636-650, 637-651,638-652, 639-653, 640-654, 641-655, 642-656, 643-657, 644-658, 645-659,646-660, 647-661, 648-662, 649-663, 650-664, 651-665, 652-666, 653-667,654-668, 655-669, 656-670, 657-671, 658-672, 659-673, 660-674, 661-675,662-676, 663-677, 664-678, 665-679, 666-680, 667-681, 668-682, 669-683,670-684, 671-685, 672-686, 673-687, 674-688, 675-689, 676-690, 677-691,678-692, 679-693, 680-694, 681-695, 682-696, 683-697, 684-698, 685-699,686-700, 687-701, 688-702, 689-703, 690-704, 691-705, 692-706, 693-707,694-708, 695-709, 696-710, 697-711, 698-712, 699-713, 700-714, 701-715,702-716, 703-717, 704-718, 705-719, 706-720, 707-721, 708-722, 709-723,710-724, 711-725, 712-726, 713-727, 714-728, 715-729, 716-730, 717-731,718-732, 719-733, 720-734, 721-735, 722-736, 723-737, 724-738, 725-739,726-740, 727-741, 728-742, 729-743, 730-744, 731-745, 732-746, 733-747,734-748, 735-749, 736-750, 737-751, 738-752, 739-753, 740-754, 741-755,742-756, 743-757, 744-758, 745-759, 746-760, 747-761, 748-762, 749-763,750-764, 751-765, 752-716, 753-767, 754-768, 755-769, 756-770, 757-771,758-772, 759-773, 760-774, 761-775, 762-776, 763-777, 764-778, 765-779,766-780, 767-781, 768-782, 769-783, 770-784, 771-785, 772-786, 773-787,774-788, 775-789, 776-790, 777-791, 778-792, 779-793, 780-794, 781-795,782-796, 783-797, 784-798, 785-799, 786-800, 787-801, 788-802, 789-803,790-804, 791-805, 792-806, 793-807, 794-808, 795-809, 796-810, 797-811,798-812, 799-813, 800-814, 801-815, 802-816, 803-817, 804-818, 805-819,806-820, 807-821, 808-822, 809-823, 810-824, 811-825, 812-826, 813-827,814-828, 815-829, 816-830, 817-831, 818-832, 819-833, 820-834, 821-835,822-836, 823-837, 824-838, 825-839, 826-840, 827-841, 828-842, 829-843,830-844, 831-845, 832-846, 833-847, 834-848, 835-849, 836-850, 837-851,838-852, 839-853, 840-854, 841-855, 842-856, 843-857, 844-858, 845-859,846-860, 847-861, 848-862, 849-863, 850-864, 851-865, 852-866, 853-867,854-868, 855-869, 856-870, 857-871, 858-872, 859-873, 860-874, 861-875,862-876, 863-877, 864-878, 865-879, 866-880, 867-881, 868-882, 869-883,870-884, 871-885, 872-886, 873-887, 874-888, 875-889, 876-890, 877-891,878-892, 879-893, 880-894, 881-895, 882-896, 883-897, 884-898, 885-899,886-990, 887-901, 888-902, 889-903, 890-904, 891-905, 892-906, 893-907,894-908, 895-909, 896-910, 897-911, 898-912, 899-913, 900-914, 901-915,902-916, 903-917, 904-918, 905-919, 906-920, 907-921, 908-922, 909-923,910-924, 911-925, 912-926, 913-927, 914-928, 915-929, 916-930, 917-931,918-932, 919-933, 920-934, 921-935, 922-936, 923-937, 924-938, 925-939,926-940, 927-941, 928-942, 929-943, 930-944, 931-945, 932-946, 933-947,934-948, 935-949, 936-950, 937-951, 938-952, 939-953, 940-954, 941-955,942-956, 943-957, 944-958, 945-959, 946-960, 947-961, 948-962, 949-963,950-964, 951-965, 952-966, 953-967, 954-968, 955-969, 956-970, 957-971,958-972, 959-973, 960-974, 961-975, 962-976, 963-977, 964-978, 965-979,966-980, 967-981, 968-982, 969-983, 970-984, 971-985, 972-986, 973-987,974-988, 975-989, 976-990, 977-991, 978-992, 979-993, 980-994, 981-995,982-996, 983-997, 984-998, 985-999, 986-1000, 987-1001, 988-1002,989-1003, 990-1004, 991-1005, 992-1006, 993-1007, 994-1008, 995-1009,996-1010, 997-1011, 998-1012, 999-1013, 1000-1014, 1001-1015, 1002-1016,1003-1017, 1004-1018, 1005-1019, 1006-1020, 1007-1021, 1008-1022,1009-1023, 1010-1024, 1011-1025, 1012-1026, 1013-1027, 1014-1028,1015-1029, 1016-1030, 1017-1031, 1018-1032, 1019-1033, 1020-1034,1021-1035, 1022-1036, 1023-1037, 1024-1038, 1025-1039, 1026-1040,1027-1041, 1028-1042, 1029-1043, 1030-1044, 1031-1045, 1032-1046,1033-1047, 1034-1048, 1035-1049, 1036-1050, 1037-1051, 1038-1052,1039-1053, 1040-1054, 1041-1055, 1042-1056, 1043-1057, 1044-1058,1045-1059, 1046-1060, 1047-1061, 1048-1062, 1049-1063, 1050-1064,1051-1065, 1052-1066, 1053-1067, 1054-1068, 1055-1069, 1056-1070,1057-1071, 1058-1072, 1059-1073, 1060-1074, 1061-1075, 1062-1076,1063-1077, 1064-1078, 1065-1079, 1066-1080, 1067-1081, 1068-1082,1069-1083, 1070-1084, 1071-1085, 1072-1086, 1073-1087, 1074-1088,1075-1089, 1076-1090, 1077-1091, 1078-1092, 1079-1093, 1080-1094,1081-1095, 1082-1096, 1083-1097, 1084-1098, 1085-1099, 1086-1100,1087-1101, 1088-1102, 1089-1103, 1090-1104, 1091-1105, 1092-1106,1093-1107, 1094-1108, 1095-1109, 1096-1110, 1097-1111, 1098-1112,1099-1113, 1100-1114, 1101-1115, 1102-1116, 1103-1117, 1104-1118,1105-1119, 1106-1120, 1107-1121, 1108-1122, 1109-1123, 1110-1124,1111-1125, 1112-1126, 1113-1127, 1114-1128, 1115-1129, 1116-1130,1117-1131, 1118-1132, 1119-1133, 1120-1134, 1121-1135, 1122-1136,1123-1137, 1124-1138, 1125-1139, 1126-1140, 1127-1141, 1128-1142,1129-1143, 1130-1144, 1131-1145, 1132-1146, 1133-1147, 1134-1148,1135-1149, 1136-1150, 1137-1151, 1138-1152, 1139-1153, 1140-1154,1141-1155, 1142-1156, 1143-1157, 1144-1158, 1145-1159, 1146-1160,1147-1161, 1148-1162, 1149-1163, 1150-1164, 1151-1165, 1152-1166,1153-1167, 1154-1168, 1155-1169, 1156-1170, 1157-1171, 1158-1172,1159-1173, 1160-1174, 1161-1175, 1162-1176, 1163-1177, 1164-1178,1165-1179, 1166-1180, 1167-1181, 1168-1182, 1169-1183, 1170-1184,1171-1185, 1172-1186, 1173-1187, 1174-1188, 1175-1189, 1176-1190,1177-1191, 1178-1192, 1179-1193, 1180-1194, 1181-1195, 1182-1196,1183-1197, 1184-1198, 1195-1199, 1186-1200, 1187-1201, 1188-1202,1189-1203, 1190-1204, 1191-1205, 1192-1206, 1193-1207, 1194-1208,1195-1209, 1196-1210, 1197-1211, 1198-1212, 1199-1213, 1200-1214,1201-1215, 1202-1216, 1203-1217, 1204-1218, 1205-1219, 1206-1220,1207-1221, 1208-1222, 1209-1223, 1210-1224, 1211-1225, 1212-1226,1213-1227, 1214-1228, 1215-1229, 1216-1230, 1217-1231, 1218-1232,1219-1233, 1220-1234, 1221-1235, 1222-1236, 1223-1237, 1224-1238,1225-1239, 1226-1240, 1227-1241, 1228-1242, 1229-1243, 1230-1244,1231-1245, 1232-1246, 1233-1247, 1234-1248, 1235-1249, 1236-1250,1237-1251, 1738-1252, 1239-1253, 1240-1254, 1241-1255, 1242-1256,1243-1257, 1244-1258, 1245-1259, 1246-1260, 1247-1261, 1248-1262,1249-1263, 1250-1264, 1251-1265, 1252-1266, 1253-1267, 1254-1268,1255-1269, 1256-1270, 1257-1271, 1258-1272, 1259-1273, 1260-1274,1261-1275, 1262-1276, 1263-1277, 1264-1278, 1265-1279, 1266-1280,1267-1281, 1268-1282, 1269-1283, 1270-1284, 1271-1285, 1272-1286,1273-1287, 1274-1288, 1275-1289, 1276-1290, 1277-1291, 1278-1292,1279-1293, 1280-1294, 1281-1295, 1282-1296, 1283-1297, 1284-1298,1285-1299, 1286-1300, 1287-1301, 1288-1302, 1289-1303, 1290-1304,1291-1305, 1292-1306, 1293-1307, 1294-1308, 1295-1309, 1296-1310,1297-1311, 1298-1312, 1299-1313, 1300-1314, 1301-1315, 1302-1316,1303-1317, 1304-1318, 1305-1319, 1306-1320, 1307-1321, 1308-1322,1309-1323, 1310-1324, 1311-1325, 1312-1326, 1313-1327, 1314-1328,1315-1329, 1316-1330, 1317-1331, 1318-1332, 1319-1333, 1320-1334,1321-1335, 1322-1336, 1323-1337, 1324-1338, 1325-1339, 1326-1340,1327-1341, 1328-1342, 1329-1343, 1330-1344, 1331-1345, 1332-1346,1333-1347, 1334-1348, 1335-1349, 1336-1350, 1337-1351, 1338-1352,1339-1353, 1340-1354, 1341-1355, 1342-1356, 1343-1357, 1344-1358,1345-1359, 1346-1360, 1347-1361, 1348-1362, 1349-1363, 1350-1364,1351-1365, 1352-1366, 1353-1367, 1354-1368, 1355-1369, 1356-1370,1357-1371, 1358-1372, 1359-1373, 1360-1374, 1361-1375, 1362-1376,1363-1377, 1364-1378, 1365-1379, 1366-1380, 1367-1381, 1368-1382,1369-1383, 1370-1384, 1371-1385, 1372-1386, 1373-1387, 1374-1388,1375-1389, 1376-1390, 1377-1391, 1378-1392, 1379-1393, 1380-1394,1381-1395, 1382-1396, 1383-1397, 1384-1398, 1385-1399, 1386-1400,1387-1401, 1388-1402, 1389-1403, 1390-1404, 1391-1405, 1392-1406,1393-1407, 1394-1408, 1395-1409, 1396-1410, 1397-1411, 1398-1412,1399-1413, 1400-1414, 1401-1415, 1402-1416, 1403-1417, 1404-1418,1405-1419, 1406-1420, 1407-1421, 1408-1422, 1409-1423, 1410-1424,4111-1425, 1412-1426, 1413-1427, 1414-1428, 1415-1429, 1416-1430,1417-1431, 1418-1432, and 1419-1433 of SEQ ID NO:1.

EXAMPLE 7 Antisense Oligonucleotides of IGFBP3

Antisense oligonucleotides to IGFBP3 may be selected from moleculescapable of interacting with one or more oligonucleotides sclected fromoligonucleotides having the sequence of nucleotides 1-15, 2-16, 3-17,4-18, 5-19, 6-20, 7-21, 8-22, 9-23, 10-24, 11-25, 12-26, 13-27, 14-28,15-29, 16-30, 17-31, 18-32, 19-33, 20-34, 21-35, 22-36, 23-37, 24-38,25-39, 26-40, 27-41, 28-42, 29-43, 30-44, 31-45, 32-46, 33-47, 34-48,35-49, 36-50, 37-51, 38-52, 39-53, 40-54, 41-55, 42-56, 43-57, 44-58,45-59, 46-60, 47-61, 48-62, 49-63, 50-64, 51-65, 52-66, 53-67, 54-68,55-69, 56-70, 57-71, 58-72, 59-73, 60-74, 61-75, 62-76, 63-77, 64-78,65-79, 66-80, 67-81, 68-82, 69-83, 70-84, 71-85, 72-86, 73-87, 74-88,75-89, 76-90, 77-91, 78-92, 79-93, 80-94, 81-95, 82-96, 83-97, 84-98,85-99, 86-100, 87-101, 88-102, 89-103, 90-104, 91-105, 92-106, 93-107,94-108, 95-109, 96-110, 97-111, 98-112, 99-113, 100-114, 101-115,102-116, 103-117, 104-118, 105-119, 106-120, 107-121, 108-122, 109-123,110-124, 111-125, 112-126, 113-127, 114-128, 115-129, 116-130, 117-131,118-132, 119-133, 120-134, 121-135, 122-136, 123-137, 124-138, 125-139,126-140, 127-141, 128-142, 129-143, 130-144, 131-145, 132-146, 133-147,134-148, 135-149, 136-150, 137-151, 138-152, 139-153, 140-154, 141-155,142-156, 143-157, 144-158, 145-159, 146-160, 147-161, 148-162, 149-163,150-164, 151-165, 152-166, 153-167, 154-168, 155-169, 156-170, 157-171,158-172, 159-173, 160-174, 161-175, 162-176, 163-177, 164-178, 165-179,166-180, 167-181, 168-182, 169-183, 170-184, 171-185, 172-186, 173-187,174-188, 175-189, 176-190, 177-191, 178-192, 179-193, 180-194, 181-195,182-196, 183-197, 184-198, 185-199, 86-200, 187-201, 188-202, 199-203,190-204, 191-205, 192-206, 193-207, 194-208, 195-209, 196-210, 197-211,198-212, 199-213, 200-214, 201-215, 202-216, 203-217, 204-218, 205-219,206-220, 207-221, 208-222, 209-223, 210-224, 211-225, 212-226, 213-227,214-228, 215-229, 216-230, 217-231, 218-232, 219-233, 220-234, 221-235,222-236, 223-237, 224-238, 225-239, 226-240, 227-241, 228-242, 229-243,230-244, 231-245, 232-246, 233-247, 234-248, 235-249, 236-250, 237-251,238-252, 239-253, 240-254, 241-255, 242-256, 243-257, 244-258, 245-259,246-260, 247-261, 248-262, 249-263, 250-264, 251-265, 252-266, 253-267,254-268, 255-269, 256-270, 257-271, 258-272, 259-273, 260-274, 261-275,262-276, 263-277, 264-278, 265-279, 266-280, 267-281, 268-282, 269-283,270-284, 271-285, 272-286, 273-287, 274-288, 275-289, 276-290, 277-291,278-292, 279-293, 280-294, 281-295, 282-296, 283-297, 284-298, 285-299,286-300, 287-301, 288-302, 289-303, 290-304, 291-305, 292-306, 293-307,294-308, 295-309, 296-310, 297-311, 298-312, 299-313, 300-314, 301-315,302-316, 303-317, 304-318, 305-319, 306-320, 307-321, 308-322, 309-323,310-324, 311-325, 312-326, 313-327, 314-328, 315-329, 316-330, 317-331,318-332, 319-333, 320-334, 321-335, 322-336, 323-337, 324-338, 325-339,326-340, 327-341, 328-342, 329-343, 330-344, 331-345, 332-346, 333-347,334-348, 335-349, 336-350, 337-351, 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1466-1480, 1467-1481, 1468-1482, 1409-1483, 1470-1484,1471-1485, 1472-1486, 1473-1487, 1474-1488, 1475-1489, 1476-1490,1477-1491, 1478-1492, 1479-1493, 1480-1494, 1481-1495, 1482-1496,1483-1497, 1484-1498, 1485-1499, 1486-1500, 1487-1501, 1488-1502,1489-1503, 1490-1504, 1491-1505, 1492-1506, 1493-1507, 1494-1508,1495-1509, 1496-1510, 1497-1511, 1498-1513, 1499-1514, 1500-1515,1501-1515, 1502-1516, 1503-1517, 1504-1518, 1505-1519, 1506-1520,1507-1521, 1508-1522, 1509-1523, 1510-1524, 1511-1525, 1512-1526,1513-1527, 1514-1528, 1515-1529, 1516-1530, 1517-1531, 1518-1532,1519-1533, 1520-1534, 1521-1535, 1522-1536, 1523-1537, 1524-1538,1525-1539, 1526-1540, 1527-1541, 1528-1542, 1529-1543, 1530-1544,1531-1545, 1532-1546, 1533-1547, 1534-1548, 1535-1549, 1536-1550,1537-1551, 1538-1552, 1539-1553, 1540-1554, 1541-1555, 1542-1556,1543-1557, 1544-1558, 1545-1559, 1546-1560, 1547-1561, 1548-1562,1549-1563, 1550-1564, 1551-1565, 1552-1566, 1553-1567, 1554-1568,1555-1569, 1556-1570, 1557-1571, 1558-1572, 1559-1573, 1560-1574,1561-1575, 1562-1576, 1563-1577, 1564-1578, 1565-1579, 1566-1580,1567-1581, 1568-1582, 1569-1583, 1570-1584, 1571-1585, 1572-1586,1573-1587, 1574-1588, 1575-1589, 1576-1590, 1577-1591, 1578-1592,1579-1593, 1580-1594, 1581-1595, 1582-1596, 1583-1597, 1584-1598,1585-1599, 1536-1600, 1587-1601, 1588-1602, 1589-1603, 1590-1604,1591-1605, 1592-1606, 1593-1607, 1594-1608, 1595-1609, 1596-1610,1597-1611, 1598-1612, 1599-1613, 1600-1614, 1601-1615, 1602-1616,1603-1617, 1604-1618, 1605-1619, 1606-1620, 1607-1621, 1608-1622,1609-1623, 1610-1624, 1611-1625, 1612-1626, 1613-1627, 1614-1628,1615-1629, 1616-1630, 1617-1631, 1618-1632, 1619-1633, 1620-1634,1621-1635, 1622-1636, 1623-1637, 1624-1638, 1625-1639, 1626-1640,1627-1641, 1628-1642, 1629-1643, 1630-1644, 1631-1645, 1632-1646,1633-1647, 1634-1648, 1635-1649, 1636-1650, 1637-1651, 1638-1652,1639-1653, 1640-1654, 1641-1655, 1642-1656, 1643-16577 1644-1658,1645-1659, 1646-1660, 1647-1661, 1648-1662, 1649-1663, 1630-1664,1651-1665, 1652-1666, 1653-1667, 1654-1668, 1655-1669, 1656-1670,1657-1671, 1658-1672, 1659-1673, 1660-1674, 1661-1675, 1662-1676,1663-1677, 1064-1678, 1665-1679, 1666-1680, 1667-1681, 1668-1682,1669-1683, 1670-1684, 1671-1685, 1672-1686, 1673-1687, 1674-1688,1675-1689, 1676-1690, 1677-1691, 1678-1692, 1679-1693, 1680-1694,1681-1695, 1682-1696, 1683-1697, 1684-1698, 1685-1699, 1686-1700,1687-1701, 1688-1702, 1689-1703, 1690-1704, 1691-1705, 1692-1706,1693-1707, 1694-1708, 1695-1709, 1696-1710, 1697-1711, 1698-1712,1699-1713, 1700-1714, 1701-1715, 1702-1716, 1703-1717, 1704-1718,1705-1719, 1706-1720, 1707-1721, 1708-1722, 1709-1723, 1710-1724,1711-1725, 1712-1726, 1713-1727, 1714-1728, 1715-1729, 1716-1730,1717-1731, 1718-1732, 1719-1733, 1720-1734, 1721-1735, 1722-1736,1723-1737, 1724-1738, 1725-1739, 1726-1740, 1727-1741, 1728-1742,1729-1743, 1730-1744, 1731-1745, 1732-1746, 1733-1747, 1734-1748,1735-1749, 1736-1750, 1737-1751, 1738-1752, 1739-1753, 1740-1754,1741-1755, 1742-1756, 1743-1757, 1744-1758, 1745-1759, 1746-1760,1747-1761, 1748-1762, 1749-1763, 1750-1764, 1751-1765, 1752-1766,1753-1767, 1754-1768, 1755-1769, 1756-1770, 1757-1771, 1758-1772,1759-1773, 1760-1774, 1761-1775, 1762-1776, 1763-1777, 1764-1778,1765-1779, 1766-1780, 1767-1781, 1768-1782, 1769-1783, 1770-1784,1771-1785, 1772-1786, 1773-1787, 1774-1788, 1775-1789, 1776-1790,1777-1791, 1778-1792, 1779-1793, 1780-1794, 1781-1795, 1782-1796,1783-1797, 1784-1798, 1785-1799, 1786-1800, 1787-1801, 1788-1802,1789-1803, 1790-1804, 1791-1805, 1792-1806, 1793-1807, 1794-1808,1795-1809, 1796-1810, 1797-1811, 1798-1812, 1799-1813, 1800-1814,1801-1815, 1802-1816, 1803-1817, 1804-1818, 1805-1819, 1806-1820,1807-1821, 1808-1822, 1809-1823, 1810-1824, 1811-1825, 1812-1826,1813-1827, 1814-1828, 1815-1829, 1816-1830, 1817-1831, 1818-1832,1819-1833, 1820-1834, 1821-1835, 1822-1836, 1823-1837, 1824-1838,1825-1839, 1826-1840, 1827-1841, 1828-1842, 1829-1843, 1830-1844,1831-1845, 1832-1846, 1833-1847, 1834-1848, 1835-1849, 1836-1850,1837-1851, 1838-1852, 1839-1853, 1840-1854, 1841-1855, 1842-1856,1843-1857, 1844-1858, 1845-1859, 1846-1860, 1847-1861, 1848-1862,1849-1863, 1850-1864, 1851-1865, 1852-1866, 1853-1867, 1854-1868,1855-1869, 1856-1870, 1857-1871, 1858-1872, 1859-1873, 1860-1874,1861-1875, 1862-1876, 1863-1877, 1864-1878, 1865-1879, 1866-1880,1867-1881, 1868-1882, 1869-1883, 1870-1884, 1871-1885, 1872-1886,1873-1887, 1874-1888, 1875-1889, 1876-1890, 1877-1891, 1878-1892,1879-1893, 1880-1894, 1881-1895, 1882-1896, 1883-1897, 1884-1898,1885-1899, 1886-1900, 1887-1901, 1888-1902, 1889-1903, 1890-1904,1891-1905, 1892-1906, 1893-1907, 1894-1908, 1895-1909, 1896-1910,1897-1911, 1898-1912, 1899-1913, 1900-1914, 1901-1915, 1902-1916,1903-1917, 1904-1918, 1905-1919, 1906-1920, 1907-1921, 1908-1922,1909-1923, 1910-1924, 1911-1925, 1912-1926, 1913-1927, 1914-1928,1915-1929, 1916-1930, 1917-1931, 1918-1932, 1919-1933, 1920-1934,1921-1935, 1922-1936, 1923-1937, 1924-1938, 1925-1939, 1926-1940,1927-1941, 1928-1942, 1929-1943, 1930-1944, 1931-1945, 1932-1946,1933-1947, 1934-1948, 1935-1949, 1936-1950, 1937-1951, 1938-1952,1939-1953, 1940-1954, 1941-1955, 1942-1956, 1943-1957, 1944-1958,1945-1959, 1946-1960, 1947-1961, 1948-1962, 1949-1963, 1950-1964,1151-1965, 1952-1966, 1953-1967, 1954-1968, 1955-1969, 1956-1970,1957-1971, 1958-1972, 1959-1973, 1960-1974, 1961-1975, 1962-1976,1963-1977, 1964-1978, 1965-1979, 1966-1980, 1967-1981, 1968-1982,1969-1983, 1970-1984, 1971-1985, 1972-1986, 1973-1987, 1974-1988,1975-1989, 1976-1990, 1977-1991, 1978-1992, 1979-1993, 1980-1994,1981-1995, 1982-1996, 1983-1997, 1984-1998, 1985-1999, 1986-2000,1987-2001, 1988-2002, 1989-2003, 1990-2004, 1991-2005, 1992-2006,1993-2007, 1994-2008, 1995-2009, 1996-2010, 1997-2011, 1998-2012,1999-2013, 2000-2014, 2001-2015, 2002-2016, 2003-2017, 2004-2018,2005-2019, 2006-2020, 2007-2021, 2008-2022, 2009-2023, 2010-2024,2011-2025, 2012-2026, 2013-2027, 2014-2028, 2015-2029, 2016-2030,2017-2031, 2018-2032, 2019-2033, 2020-2034, 2021-2035, 2022-2036,2023-2037, 2024-2038, 2025-2039, 2026-2040, 2027-2041, 2028-2042,2029-2043, 2030-2044, 2031-2045, 2032-2046, 2033-2047, 2034-2048,2035-2049, 2036-2050, 2037-2051, 2038-2052, 2039-2053, 2040-2054,2041-2055, 2042-2056, 2043-2057, 2044-2058, 2045-2059, 2046-2060,2047-2061, 2048-2062, 2049-2063, 2050-2064, 2051-2065, 2052-2066,2053-2067, 2054-2068, 2055-2069, 2056-2070, 2057-2071, 2058-2072,2059-2073, 7060-2074, 2061-2075, 2062-2076, 2063-2077, 2064-2078,2065-2079, 2066-2080, 2067-2081, 2068-2082, 2069-2083, 2070-2084,2071-2085, 2072-2086, 2073-2087, 2074-2088, 2075-2089, 2076-2090,2077-2091, 2078-2092, 2079-2093, 2080-2094, 2081-2095, 2082-2096.2083-2097, 2084-2098, 2085-2099, 2086-2100, 2087-2101, 2088-2102,2089-2103, 2090-2104, 2091-2105, 2092-2106, 2093-2107, 2094-2108,2095-2109, 2096-2110, 2097-2111, 2098-2112, 2099-2113, 2100-2114,2101-2115, 2102-2116, 2103-2117, 2104-2118, 2105-2119, 2106-2120,2107-2121, 2108-2122, 2109-2123, 2110-2124, 2111-2125, 2112-2126,2113-2127, 2114-2128, 2115-2129, 2116-2130, 2117-2131, 2118-2132,2119-2133, 2120-2134, 2121-2135, 2122-2136, 2123-2137, 2124-2138,2125-2139, 2126-2140, 2127-2141, 2128-2142, 2129-2143, 2130-2144,2131-2145, 2132-2146, 2133-2147, 2134-2148, 2135-2149, 2136-2150,2137-2151, 2138-2152, 2139-2153, 2140-2154, 2141-2155, 2142-2156,2143-2157, 2144-2158, 2145-2159, 2146-2160, 2147-2161, 2148-2162,2149-2163, 2150-2164, 2151-2165, 2152-2166, 2153-2167 2154-2168,2155-2169, 2156,-2170, 2157-2171, 2158-2172, 2159-2173, 2160-2174,2161-2175, 2162-2176, 2163-2177, 2164-2178, 2165-2179, 2166-2180,2167-2181, 2168-2182, 2169-2183, 2170-2184, 2171-2185, 2172-2186,2173-2187, 2174-2188, 2175-2189, 2176-2190, 2177-2191, 2178-2192,2179-2913, 2180-2194, 2181-2195, 2182-2196, 2183-2197, 2184-2198,2185-2199, 2186-2200, 2187-2201, 2188-2202, 2129-2203, 2190-2204,2191-2205, 2192-2206, 2193-2207, 2194-2208, 2195-2209, 2196-2210,2197-2211, 2198-2212, 2199-2213, 2200-2214, 2201-2215, 2202-2216,2203-2217, 2214-2218, 2205-2219, 2206-2220, 2227-2221, 2208-2222,2209-2223, 2210-2224, 2211-2225, 2212-2226, 2213-2227, 2214-2228,2215-2229, 2216-2230, 2217-2231, 2218-2232, 2219-2233, 2220-2234,2221-2235, 2222-2236, 2223-2237, 2224-2238, 2225-2239, 2226-2240,2227-2241, 2228-2242, 2229-2243, 2230-2244, 2231-2245, 2232-2246,2213-2247, 2234-2248, 2235-2249, 2236-2250, 2237-2251, 2238-2252,2239-2253, 2240-2254, 2241-2255, 2242-2256, 2243-2257, 2244-2258,2245-2259, 2246-2260, 2247-2261, 2248-2262, 2249-2263, 2250-2264,2251-2265, 2252-2266, 2253-2267, 2254-2268, 2255-2269, 2256-2270,2257-2271, 2258-2272, 2259-2273, 2260-2274, 2261-2275, 2262-2276,2263-2277, 2264-2278, 2265-2279, 2266-2280, 2267-2281, 2268-2282,2269-2283, 2270-2284, 2271-2283, 2272-2286, 2273-2287, 2274-2288,2275-2289, 2276-2290, 2277-2291, 2278-2299, 2279-2293, 2280-2294,2281-2295, 2282-2296, 2283-2297, 2284-2298, 2285-2299, 2286-2300,2287-2301, 2288-2302, 2289-2303, 2290-2304, 2291-2305, 2292-2306,2293-2307, 2294-2308, 2295-2309, 2296-2310, 2297-2311, 2298-2312,2299-2313, 2300-2314, 2301-2315, 2302-2315, 2303-2317, 2304-2318,2305-2319, 2306-2320, 2307-2321, 2308-2322, 2309-2323, 2310-2324,2311-2325, 2312-2326, 2313-2327, 2314-2328, 2315-2329, 2316-2330,2317-2331, 2318-2332, 2319-2333, 2320-2334, 2321-2335, 2322-2336,2323-2337, 2324-2338, 2325-2339, 2326-2340, 2327-2341, 2328-2342,2329-2343, 2330-2344, 2331-2345, 2332-2346, 2333-2347, 2334-2348,2335-2349, 2336-2350, 2337-2351, 2338-2352, 2339-2353, 2340-2354,2341-2355, 2342-2356, 2343-2357, 2344-2358, 2345-2359, 2346-2360,2347-2361, 2348-2362, 2349-2363, 2350-2364, 2351-2365, 2352-2366,2353-2367, 2354-2368, 2355-2369, 2356-2370, 2357-2371, 2358-2372,2359-2373, 2360-2374, 2361-2375, 2362-2376, 2363-2377, 2364-2378,2365-2379, 2366-2380, 2367-2381, 2368-2382, 2369-2383, 2370-2384,2371-2385, 2372-2386, 2373-2387, 2374-2388, 2375-2389, 2376-2390,2377-2391, 2378-2392, 2379-2393, 2380-2394, 2381-2395, 2382-2396,2383-2397, 2384-2398, 2385-2399, 2386-2400, 2387-2401, 2388-2402,2389-2403, 2390-2404, 2391-2405, 2392-2406, 2393-2407, 2394-2408,2395-2409, 2396-2410, 2397-2411, 2398-2412, 2399-2413, 2400-1412,2401-2415, 2402-2416, 2403-2417, 2404-2418, 2405-2419, 2406-2420,2407-2421, 2408-2422, 2409-2423, 2410-2424, 2411-2425, 2412-2426,2413-2427, 2414-2428, 2415-2429, 2416-2430, 2417-2431, 2418-2432,2419-2433, 2420-2434, 2421-2435, 2422-2436, 2423-2437, 2424-2438,2425-2439, 2426-2440, 2427-2441, 2428-2442, 2429-2443, 2430-2444,2431-2445, 2432-2446, 2433-2447, 2434-2448, 2435-2449, 2436-2450,2437-2451, 2438-2452, 2439-2453, 2440-2454, 2441-2455, 2442-2456,2443-2457, 2444-2458, 2445-2459, 2446-2460, 2447-2461, 2448-2462,2449-2463, 2450-2464, 2451-2465, 2452-2466, 2453-2467, 2454-2468,2455-2469, 2456-2470, 2457-2471, 2458-2472, 2459-2437, and 2460-2474 ofSEQ ID NO:2.

EXAMPLE 8 Antisense Oligonucleotides of IGF-I Receptor

Antisense oligonucleotides to IGF-I receptor may be selected frommolecules capable of interacting with one or more oligonucleotidesselected from oligonucleotides having the sequence of nucleotides 1-15,2-16, 35-17, 4-18, 5-19, 6-20, 7-21, 8-22, 9-23, 10-24, 11-25, 12-26,13-27, 14-28, 15-29, 16-30, 17-31, 18-32, 19-33, 20-34, 21-35, 22-36,23-37, 24-38, 25-39, 26-40, 27-41, 28-42, 29-43, 30-44, 31-45, 32-46,33-47, 34-48, 35-49, 36-50, 37-51, 38-52, 39-53, 40-54, 41-55, 42-56,43-57, 44-58, 45-59, 46-60, 47-61, 48-62, 49-63, 50-64, 51-65, 52-66,53-67, 54-68, 55-69, 56-70, 57-71, 58-72, 59-73, 60-74, 61-75, 62-76,63-77, 64-78, 65-79, 66-80, 67-81, 68-82, 69-83, 70-84, 71-85, 72-86,73-87, 74-88, 75-89, 76-90, 77-91, 78-92, 79-93, 80-94, 81-95, 82-96,83-97, 84-98, 85-99, 86-100, 87-101, 88-102, 89-103, 90-104, 91-105,92-106, 93-107, 94-108, 95-109, 96-110, 97-111, 98-112, 99-113, 100-114,101-115, 102-116, 103-117, 104-118, 105-119, 106-120, 107-121, 108-122,109-123, 110-124, 111-125, 112-126, 113-127, 114-128, 115-129, 116-130,117-131, 118-132, 119-133, 120-134, 121-135, 122-136, 123-137, 124-138,125-139, 126-140, 127-141, 128-142, 129-143, 130-144, 131-145, 132-146,133-147, 134-148, 135-149, 136-150, 137-151, 138-152, 139-153, 140-154,141-155, 142-156, 143-157, 144-158, 145-159, 146-160, 147-161, 148-162,149-163, 150-164, 151-165, 152-166, 153-167, 154-168, 155-169, 156-170,157-171, 158-172, 159-173, 160-174, 161-175, 162-176, 163-177, 164-178,165-179, 166-180, 167-181, 168-182, 169-183, 170-184, 171-185, 172-186,173-187, 174-188, 175-189, 176-190, 177-191, 178-192, 179-193, 180-194,181-195, 182-196, 183-197, 184-198, 185-199, 186-200, 187-201, 188-202,189-203, 190-204, 191-205, 192-206, 193-207, 194-208, 195-209, 196-210,197-211, 198-212, 199-213, 200-214, 201-215, 202-216, 203-217, 204-218,205-219, 206-220, 207-221, 208-222, 209-223, 210-224, 211-225, 212-226,213-227, 214-228, 215-229, 216-230, 217-231, 218-232, 219-233, 220-234,221-235, 222-236, 223-237, 224-238, 225-239, 226-240, 227-241, 228-242,229-243, 230-244, 231-245, 232-246, 233-247, 234-248, 235-249, 236-250,237-251, 238-252, 239-253, 240-254, 241-255, 242-256, 243-257, 244-258,245-259, 246-260, 247-261, 248-262, 249-263, 250-264, 251-265, 252-266,253-267, 254-268, 255-269, 256-270, 257-271, 258-272, 259-273, 260-274,261-275, 262-276, 263-277, 264-278, 265-279, 266-280, 267-281, 268-282,269-283, 270-284, 271-285, 272-286, 273-287, 274-288, 275-289, 276-290,277-291, 278-292, 279-293, 280-294, 281-295, 282-296, 283-297, 284-298,285-299, 286-300, 287-301, 288-302, 289-303, 290-304, 291-305, 212-306,293-307, 294-308, 295-309, 296-310, 297-311, 298-312, 299-313, 300-314,301-315, 302-315, 303-317, 304-318, 305-319, 306-320, 307-321, 308-322,309-323, 310-324, 311-325, 312-326, 313-327, 314-328, 315-329, 316-330,317-331, 318-332, 319-333, 320-334, 321-335, 322-336, 323-337, 324-338,325-339, 326-340, 327-341, 328-342, 329-343, 330-344, 331-345, 332-346,333-347, 334-348, 335-349, 336-350, 337-351, 338-352, 339-353, 340-354,341-355, 342-356, 343-357, 344-358, 345-359, 346-360, 347-361, 348-362,349-363, 330-364, 351-365, 352-366, 353-367, 354-368, 355-369, 356-370,357-371, 358-172, 359-373, 360-374, 361-375, 362-376, 363-377, 364-378,365-379, 366-380, 367-381, 368-382, 369-383, 370-384, 371-385, 372-386,373-387, 374-388, 375-389, 376-390, 377-391, 378-392, 379-393, 380-394,381-395, 382-396, 383-397, 384-398, 385-399, 386-400, 387-401, 388-402,389-403, 390-404, 391-405, 392-406, 393-407, 394-408, 395-409, 396-410,397-411, 398-412, 399-413, 400-414, 401-415, 402-416, 403-417, 404-418,405-419, 406-420, 407-421, 408-422, 409-423, 410-424, 411-425, 412-426,413-427, 414-428, 415-429, 416-430, 417-431, 418-432, 419-433, 420-434,421-435, 422-436, 423-437, 424-438, 425-439, 426-440, 427-441, 428-442,429-443, 430-444, 431-445, 432-446, 433-447, 434-448, 435-449, 436-450,437-451, 438-452, 439-453, 440-454, 441-455, 442-456, 443-457, 444-458,445-459, 446-460, 447-461, 448-462, 449-463, 450-464, 451-465, 452-466,453-467, 454-468, 455-469, 456-470, 457-471, 458-472, 459-473, 460-474,401-475, 462-476, 463-477, 464-478, 465-479, 466-480, 467-481, 468-482,469-483, 470-484, 471-485, 472-486, 473-487, 474-488, 475-489, 476-490,477-491, 478-492, 479-493, 480-494, 481-495, 482-496, 483-497, 484-498,485-499, 486-500, 487-501, 488-502, 489-503, 490-504, 491-505, 492-506,493-507, 494-508, 495-509, 496-510, 497-511, 498-513, 499-514, 500-515,501-515, 502-516, 503-517, 504-518, 505-519, 506-520, 507-521, 508-522,509-523, 510-524, 511-525, 512-526, 513-527, 514-528, 515-529, 516-530,517-531, 518-532, 519-533, 520-534, 521-535, 522-536, 523-537, 524-538,525-539, 526-540, 527-541, 528-542, 529-543, 530-544, 531-545, 532-546,533-547, 534-548, 535-549, 536-550, 537-551, 538-552, 539-553, 540-554,541-555, 542-556, 543-557, 544-558, 545-559, 546-560, 547-561, 548-562,549-563, 550-564, 551-565, 552-566, 553-567, 554-568, 555-569, 556-570,557-571, 558-572, 559-573, 560-574, 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4501-4515, 4502-4516, 4503-4517, 4504-4518, 4505-4519,4506-4520, 4507-4521, 4508-4522, 4509-4523, 4510-4524, 4511-4525,4512-4526, 4513-4527, 4514-4528, 4515-4529, 4516-4530, 4517-4531,4518-4532, 4519-4533, 4520-4534, 4521-4535, 4522-4536, 4523-4537,4524-4538, 4525-4539, 4526-4540, 4527-4541, 4528-4542, 4529-4543,4530-4544, 4531-4545, 4532-4546, 4533-4547, 4534-4548, 4535-4549,4536-4550, 4537-4551, 4538-4552, 4539-4553, 4540-4534, 4541-4555,4542-4556, 4543-4557, 4544-4558, 4545-4559, 4546-4560, 4547-4561,4548-4562, 4549-4563, 4550-4564, 4551-4565, 4552-4566, 4553-4567,4554-4568, 4555-4569, 4556-4570, 4557-4571, 4558-4572, 4559-4573,4560-4574, 4561-4575, 4562-4576, 4563-4577, 4564-4578, 4565-4579,4566-4580, 4567-4581, 4568-4582, 4569-4583, 4570-4584, 4571-4585,4572-4586, 4573-4587, 4574-4588, 4575-4589, 4576-4590, 4577-4591,4578-4592, 4579-4593, 4580-4594, 4581-4595, 4582-4596, 4583-4597,4584-4598, 4585-4599, 4586-4600, 4587-4601, 4588-4602, 4589-4603,4590-4604, 4591-4605, 4592-4606, 4593-4607, 4594-4608, 4595-4609,4596-4610, 4597-4611, 4598-4612, 4599-4613, 4600-4614, 4601-4615,4602-4616, 4603-4617, 4604-4618, 4605-4619, 4606-4620, 4607-4621,4608-4622, 4609-4623, 4610-4624, 4611-4625, 4612-4626, 4613-4627,4614-4628, 4615-4629, 4616-4630, 4617-4631, 4618-4632, 4619-4633,4620-4634, 4621-4635, 4622-4636, 4623-4637, 4624-4638, 4625-4639,4626-4640, 4627-4641, 4628-4642, 4629-4643, 4630-4644, 4631-4645,4632-4646, 4633-4647, 4634-4648, 4635-4649, 4636-4650, 4637-4651,4638-4652, 4639-4653, 4640-4654, 4641-4655, 4642-4656, 4643-4657,4644-4658, 4645-4659, 4646-4660, 4647-4661, 4648-4662, 4649-4663,4650-4664, 4651-4665, 4652-4666, 4653-4667, 4654-4668, 4655-4669,4656-4670, 4657-4671, 4658-4672, 4659-4673, 4660-4674, 4661-4675,4662-4676, 4663-4677, 4664-4678, 4665-4679, 4666-4680, 4667-4681,4668-4682, 4669-4683, 4670-4684, 4671-4685, 4672-4686, 4673-4687,4674-4688, 4675-4689, 4676-4690, 4677-4691, 4678-4692, 4679-4693,4680-4694, 4681-4695, 4682-4696, 4683-4697, 4684-4698, 4685-4699,4686-4700, 4687-4701, 4688-4702, 4689-4703, 4690-4704, 4691-4705,4692-4706, 4693-4707, 4694-4708, 4695-4709, 4696-4710, 4697-4711,4698-4712, 4699-4713, 4700-4714, 4701-4715, 4702-4716, 4703-4717,4704-4718, 4705-4719, 4706-4720, 4707-4721, 4708-4722, 4709-4723,4710-4724, 4711-4725, 4712-4726, 4713-4727, 4714-4728, 4715-4729,4716-4730, 4717-4731, 4718-4732, 4719-4733, 4720-4734, 4721-4735,4722-4736, 4723-4737, 4724-4738, 4725-4739, 4726-4740, 4727-4741,4728-4742, 4729-4743, 4730-4744, 4731-4745, 4732-4746, 4733-4747,4734-4748, 4735-4749, 4736-4750, 4737-4751, 4738-4752, 4739-4753,4740-4754, 4741-4755, 4742-4756, 4743-4757, 4744-4758, 4745-4759,4746-4760, 4747-4761, 4748-4762, 4749-4763, 4750-4764, 4751-4765,4752-4766, 4753-4767, 4754-4768, 4755-4769, 4756-4770, 4757-4771,4758-4772, 4759-4773, 4760-4774, 4761-4775, 4762-4776, 4763-4777,4764-4778, 4765-4779, 4766-4780, 4767-4781, 4768-4782, 4769-4783,4770-4784, 4771-4785, 4772-4786, 4773-4787, 4774-4788, 4775-4789,4776-4790, 4777-4791, 4778-4792, 4779-4793, 4780-4794, 4781-4795,4782-4796, 4783-4797, 4784-4798, 4785-4799, 4786-4800, 4787-4801,4788-4802, 4789-4803, 4790-4804, 4791-4805, 4792-4806, 4793-4807,4794-4808, 4795-4809, 4796-4810, 4797-4811, 4798-4812, 4799-4813,4800-4814, 4801-4815, 4802-4816, 4803-4817, 4804-4818, 4805-4819,4806-4820, 4807-4821, 4808-4822, 4809-4823, 4810-4824, 4811-4825,4812-4826, 4813-4827, 4814-4828, 4815-4829, 4816-4830, 4817-4831,4818-4832, 4819-4833, 4820-4834, 4821-4835, 4822-4836, 4823-4837,4824-4838, 4825-4839, 4826-4840, 4827-4841, 4828-4842, 4829-4843,4830-4844, 4831-4845, 4832-4846, 4833-4847, 4834-4848, 4835-4849,4836-4850, 4837-4851, 4838-4852, 4839-4853, 4840-4854, 4841-4855,4842-4856, 4843-4857, 4844-4858, 4845-4859, 4846-4860, 4847-4861,4848-4862, 4849-4863, 4850-4864, 4851-4865, 4852-4866, 4853-4867,4854-4868, 4855-4869, 4856-4870, 4857-4871, 4858-4872, 4859-4873,4860-4874, 4861-4875, 4862-4876, 4863-4877, 4864-4878, 4865-4879,4866-4880, 4867-4881, 4868-4882, 4869-4883, 4870-4884, 4871-4885,4872-4886, 4873-4887, 4874-4888, 4875-4889, 4876-4890, 4877-4891,4878-4892, 4879-4893, 4880-4894, 4881-4895, 4882-4896, 4883-4897,4884-4898, 4885-4899, 4886-4900, 4887-4901, 4888-4902, 4889-4903,4890-4904, 4891-4905, 4892-4906, 4893-4907, 4894-4908, 4895-4909,4896-4910, 4897-4911, 4898-4912, 4899-4913, 4900-4914, 4901-4915,4902-4916, 4903-4917, 4904-4918, 4905-4919, 4906-4920, 4907-4921,4908-4922, 4909-4923, 4910-4924, 4911-4925, 4912-4926, 4913-4927,4914-4928, 4915-4929, 4916-4930, 4917-4931, 4918-4932, 4919-4933,4920-4934, 4921-4935, 4922-4936, 4923-4937, 4924-4938, 4925-4939,4926-4940, 4927-4941, 4928-4942, 4929-4943, 4930-4944, 4931-4945,4932-4946, 4933-4947, 4934-4948, 4935-4949, 4936-4950, 4937-4951,4938-4952, 4939-4953, 4940-4954, 4941-4955, 4942-4956, 4943-4957,4944-4958, 4945-4959, 4046-4960, 4947-4961, 4948-4962, 4949-4963,4950-4964, 4951-4965, 4952-4966, 4953-4967, 4954-4968, 4955-4969,4956-4970, 4957-4971, 4958-4972, 4959-4973, 4960-4974, 4961-4975,4962-4976, 4963-4977, 4964-4978, 4965-4979, 4966-4980, 4967-4981,4968-4982, 4969-4983, 4970-4984, 4971-4985, 4972-4986, 4973-4987,4974-4988 and 4975-4989 of SEQ ID NO:3.

EXAMPLE 9 Inhibition of IGF-I Binding by Antisense Oligonucleotides toIGF-I Receptor

Sub-confluent HaCaT cells were treated as described above withphosphorothioate oligonucleotides IGFR.AS (antisense:5′-ATCTCTCCGCTTCCC-3′; [SEQ ID NO. 10]; ref 13) and IGFR.S (sensecontrol: 5′-GAAAGGAAGCGGAGAGAT-3′; [SEQ ID NO. 11]; ref 13) IGF-Ibinding to the cell monolayers was then measured as ¹²⁵I-IGF-I.

EXAMPLE 10 Inhibition of IGFBP-3 Production Using AntisenseOligonucleotides

The results of this experiment are shown in FIGS. 7 and 8.

HaCaT cells were initially plated in DMEM with 10% v/v serum, then ASoligo experiments were performed in complete “Keratinocyte-SFM” (Gibco)to exclude the influence of exogenous IGFBPs. Oligos were synthesised asphosphorothioate (nuclease-resistant) derivatives (Bresatec, SouthAustralia) and were as follows: antisense: AS2, (SEQ ID NO:4)5′-GCGCCCGCTGCATGACGCCTGCAAC-3′ (IGFBP-3 start codon); controls: AS2NS(SEQ ID NO:8), 5′-CGGAGATGCCGCATGCCAGCGCAGG-3′; AS4 (SEQ ID NO:6),5′-AGGCGGCTGACGGCACTA-3′; AS4NS (SEQ ID NO:9), 5′-GACAGCGTCGGAGCGATC-3′;IGFRAS (SEQ ID NO:10), 5′-ATCTCTCCGCTTCCTTTC-3′; IGFRS (SEQ ID NO:11),5′-GAAAGGAAGCGGAGAGAT-3′. Oligos to IGFBP-3 were based on the publishedsequence of Spratt et al [12]. AS oligos were added to HaCaT monolayersin 0.5 ml medium in 24-well plates at the concentrations and additionfrequencies indicated. IGFBP-3 measured in cell-conditioned medium usinga dot-blot assay, adapted from the Western ligand blot method ofHossenlopp et al [11], in which 100 μl of conditioned medium was appliedto nitrocellulose filters with a vacuum dot-blot apparatus. After dryingthe membranes at 37° C., relative amounts of IGFBP are determined by¹²⁵I-IGF-I-binding, autoradiography and computerised imagingdensitometry. Triplicate wells (except in FIG. 7, where duplicate wellswere measured as shown) were analysed and corrected for changes in cellnumber per well. Relative cell number per well was determined using anamido black dye method, developed specifically for cultured monolayersof HaCaT cells (14). Cell numbers differed by less than 10% aftertreatment. For oligos to the IGF receptor, receptor quantitation inintact HaCaT monolayers was by overnight incubation with ¹²⁵I-IGF-I(30,000cpm/well) at 4° C.

EXAMPLE 11 Inhibition of IGFBP-2 Production Using Ribozymes

Experiments involving ribozymes are generally conducted as described inInternaitonal Patent Application No. WO 89/05852 and in Haselhoff andGerlach [8]. Ribozymes are constructed with a hybridising region whichis complementary in nucleotide sequence to at least part of a target RNAwhich, in this case, encodes IGFBP-2. Activity of ribozymes ismeasurable on, for example, Northern blots or using animal models suchas in the nude mouse model (15; 16) or the “flaky skin” mouse model (17;18).

EXAMPLE 12 Inhibition of IGFBP-3 Production Using Ribozymes

The methods described in Example 11 are used for the screening ofribozymes which inhibit IGFBP-3 production. The activity of theribozymes is determined as in Example 11.

EXAMPLE 13 Inhibition of IGF-1 Production Using Ribozymes

The methods described in Example 11 are used for the screening ofribozymes which inhibit IGF-1 production. The activity of the ribozymesis determined as in Example 11.

EXAMPLE 14 Inhibition of IGF-1 Receptor Production Using Ribozymes

The methods described in Example 11 are used for the screening ofribozymes which inhibit IGF-1 production. The activity of the ribozymesis determined as in Example 11.

Those skilled in the art will appreciate that the invention describedherein is susceptible to variations and modifications other than thosespecifically described. It is to be understood that the inventionincludes all such variations and modifications. The invention alsoincludes all of the steps, features, compositions and compounds referredto or indicated in this specification, individually or collectively, andany and all combinations of any two or more of said steps or features.

REFERENCES

1. Sara V Physiological Reviews 70: 591-614, 1990.

2. Rechler M M and Brown A L Growth Regulation 2: 55-68, 1992.

3. Clemmons D R Growth Regn 2: 80, 1992.

4. Oakes S R, K M Haynes, M J Waters, A C Herington and G A Werther J.Clin Endocrinol Metab 73: 1368-1373, 1992.

5. Camacho-Hubner C et al. J Biol Chem 267: 11949-11956, 1992.

6. Neely K E et al. J Inv Derm 96: 104, 1991.

7. Ts'O P O P, Aurelian L, Chang E and Miller P S. Nonionicoligonucleotide analogs (Matagen T M) as anticodic agents in duplex andtriplex formation in “Antisense Strategies”, Annals of the New YorkAcademy of Sciences 660:159-177 (Baserga R and Denhardt D T, eds.),1993.

8. Haseloff J and Gerlach L Nature 334: 586-591, 1988.

9. Boukamp P, Petrussevska R T, Breitkreuz D, Hornung J, Markham A,Fusenig N E. J Cell Biol 106: 761-771, 1988.

10. Rheinwald and Green Cell 6: 331-344, 1975.

11. Hossenlopp P, Seurin D, Segovia-Quinson B, Hardouin S, Binoux M.Anal Biochem 154: 138-143, 1986.

12. Spratt S K, Tatsuno G P, Yamanaka M K, Ark B C, Detmer J,Mascarenhas D, Flynn J, Talkington-Verser C, Spencer E M. Growth Factors3: 63-72, 1990.

13. Pietrzkowski, Z, Sell C, Lammers R, Ullrich A and Baserga R. Mol.Cell. Biol. 12: 3883-3889, 1992.

14. Schulz J, Dettlaff S, Fritzsche U, Harms U, Schiebel H, Derer W,Fusenig N E, Hulsen A and Bohm M. J. Immunol. Meth. 167: 1-13, 1994.

15. Baker B S, Brent L, Valdimarsson H, Powles A V, Al-Imara L, Walker Mand Fry L. Brit. J. Bermatol 126: 105-110, 1992.

16. Nanney L B et al J. Invest. Bermatol 98: 296-301, 1992.

17. Sundberg J P et al Immunol. Investigations 22: 389-401, 1993.

18. Sundberg J P et al J. Invest. Dermatol 102: 781-788, 1994.

11 1433 base pairs nucleic acid single linear cDNA not provided CodingSequence 118...1101 (A) NAME/KEY Coding Sequence (B) LOCATION 118...234(D) OTHER INFORMATION (A) NAME/KEY Coding Sequence (B) LOCATION235...1101 (D) OTHER INFORMATION C., et al.Binkert Cloning, sequenceanalysis and expression... EMBO J. 8 1989 2497-2502 1 ATTCGGGGCGAGGGAGGAGG AAGAAGCGGA GGAGGCGGCT CCCGCTCGCA GGGCCGTGCA 60 CCTGCCCGCCCGCCCGCTCG CTCGCTCGCC CGCCGCGCCG CGCTGCCGAC CGCCAGC ATG 120 Met 1 CTGCCG AGA GTG GGC TGC CCC GCG CTG CCG CTG CCG CCG CCG CCG CTG 168 Leu ProArg Val Gly Cys Pro Ala Leu Pro Leu Pro Pro Pro Pro Leu 5 10 15 CTG CCGCTG CTG CCG CTG CTG CTG CTG CTA CTG GGC GCG AGT GGC GGC 216 Leu Pro LeuLeu Pro Leu Leu Leu Leu Leu Leu Gly Ala Ser Gly Gly 20 25 30 GGC GGC GGGGCG CGC GCG GAG GTG CTG TTC CGC TGC CCG CCC TGC ACA 264 Gly Gly Gly AlaArg Ala Glu Val Leu Phe Arg Cys Pro Pro Cys Thr 35 40 45 CCC GAG CGC CTGGCC GCC TGC GGG CCC CCG CCG GTT GCG CCG CCC GCC 312 Pro Glu Arg Leu AlaAla Cys Gly Pro Pro Pro Val Ala Pro Pro Ala 50 55 60 65 GCG GTG GCC GCAGTG GCC GGA GGC GCC CGC ATG CCA TGC GCG GAG CTC 360 Ala Val Ala Ala ValAla Gly Gly Ala Arg Met Pro Cys Ala Glu Leu 70 75 80 GTC CGG GAG CCG GGCTGC GGC TGC TGC TCG GTG TGC GCC CGG CTG GAG 408 Val Arg Glu Pro Gly CysGly Cys Cys Ser Val Cys Ala Arg Leu Glu 85 90 95 GGC GAG GCG TGC GGC GTCTAC ACC CCG CGC TGC GGC CAG GGG CTG CGC 456 Gly Glu Ala Cys Gly Val TyrThr Pro Arg Cys Gly Gln Gly Leu Arg 100 105 110 TGC TAT CCC CAC CCG GGCTCC GAG CTG CCC CTG CAG GCG CTG GTC ATG 504 Cys Tyr Pro His Pro Gly SerGlu Leu Pro Leu Gln Ala Leu Val Met 115 120 125 GGC GAG GGC ACT TGT GAGAAG CGC CGG GAC GCC GAG TAT GGC GCC AGC 552 Gly Glu Gly Thr Cys Glu LysArg Arg Asp Ala Glu Tyr Gly Ala Ser 130 135 140 145 CCG GAG CAG GTT GCAGAC AAT GGC GAT GAC CAC TCA GAA GGA GGC CTG 600 Pro Glu Gln Val Ala AspAsn Gly Asp Asp His Ser Glu Gly Gly Leu 150 155 160 GTG GAG AAC CAC GTGGAC AGC ACC ATG AAC ATG TTG GGC GGG GGA GGC 648 Val Glu Asn His Val AspSer Thr Met Asn Met Leu Gly Gly Gly Gly 165 170 175 AGT GCT GGC CGG AAGCCC CTC AAG TCG GGT ATG AAG GAG CTG GCC GTG 696 Ser Ala Gly Arg Lys ProLeu Lys Ser Gly Met Lys Glu Leu Ala Val 180 185 190 TTC CGG GAG AAG GTCACT GAG CAG CAC CGG CAG ATG GGC AAG GGT GGC 744 Phe Arg Glu Lys Val ThrGlu Gln His Arg Gln Met Gly Lys Gly Gly 195 200 205 AAG CAT CAC CTT GGCCTG GAG GAG CCC AAG AAG CTG CGA CCA CCC CCT 792 Lys His His Leu Gly LeuGlu Glu Pro Lys Lys Leu Arg Pro Pro Pro 210 215 220 225 GCC AGG ACT CCCTGC CAA CAG GAA CTG GAC CAG GTC CTG GAG CGG ATC 840 Ala Arg Thr Pro CysGln Gln Glu Leu Asp Gln Val Leu Glu Arg Ile 230 235 240 TCC ACC ATG CGCCTT CCG GAT GAG CGG GGC CCT CTG GAG CAC CTC TAC 888 Ser Thr Met Arg LeuPro Asp Glu Arg Gly Pro Leu Glu His Leu Tyr 245 250 255 TCC CTG CAC ATCCCC AAC TGT GAC AAG CAT GGC CTG TAC AAC CTC AAA 936 Ser Leu His Ile ProAsn Cys Asp Lys His Gly Leu Tyr Asn Leu Lys 260 265 270 CAG TGC AAG ATGTCT CTG AAC GGG CAG CGT GGG GAG TGC TGG TGT GTG 984 Gln Cys Lys Met SerLeu Asn Gly Gln Arg Gly Glu Cys Trp Cys Val 275 280 285 AAC CCC AAC ACCGGG AAG CTG ATC CAG GGA GCC CCC ACC ATC CGG GGG 1032 Asn Pro Asn Thr GlyLys Leu Ile Gln Gly Ala Pro Thr Ile Arg Gly 290 295 300 305 GAC CCC GAGTGT CAT CTC TTC TAC AAT GAG CAG CAG GAG GCT TGC GGG 1080 Asp Pro Glu CysHis Leu Phe Tyr Asn Glu Gln Gln Glu Ala Cys Gly 310 315 320 GTG CAC ACCCAG CGG ATG CAG TAGACCGCAG CCAGCCGGTG CCTGGCGCCC CTGC 1135 Val His ThrGln Arg Met Gln 325 CCCCCGCCCC TCTCCAAACA CCGGCAGAAA ACGGAGAGTGCTTGGGTGGT GGGTGCTGGA 1195 GGATTTTCCA GTTCTGACAC ACGTATTTAT ATTTGGAAAGAGACCAGCAC CGAGCTCGGC 1255 ACCTCCCCGG CCTCTCTCTT CCCAGCTGCA GATGCCACACCTGCTCCTTC TTGCTTTCCC 1315 CGGGGGAGGA AGGGGGTTGT GGTCGGGGAG CTGGGGTACAGGTTTGGGGA GGGGGAAGAG 1375 AAATTTTTAT TTTTGAACCC CTGTGTCCCT TTTGCATAAGATTAAAGGAA GGAAAAGT 1433 2474 base pairs nucleic acid single linear cDNAnot provided Coding Sequence 110...982 W.I., et al.Wood Cloning andexpression of the growth... Mol. Endocrinol. 2 1988 1176-1185 2CTCAGCGCCC AGCCGCTTCC TGCCTGGATT CCACAGCTTC GCGCCGTGTA CTGTCGCCCC 60ATCCCTGCGC GCCCAGCCTG CCAAGCAGCG TGCCCCGGTT GCAGGCGTC ATG CAG CGG 118Met Gln Arg 1 GCG CGA CCC ACG CTC TGG GCC GCT GCG CTG ACT CTG CTG GTGCTG CTC 166 Ala Arg Pro Thr Leu Trp Ala Ala Ala Leu Thr Leu Leu Val LeuLeu 5 10 15 CGC GGG CCG CCG GTG GCG CGG GCT GGC GCG AGC TCG GGG GGC TTGGGT 214 Arg Gly Pro Pro Val Ala Arg Ala Gly Ala Ser Ser Gly Gly Leu Gly20 25 30 35 CCC GTG GTG CGC TGC GAG CCG TGC GAC GCG CGT GCA CTG GCC CAGTGC 262 Pro Val Val Arg Cys Glu Pro Cys Asp Ala Arg Ala Leu Ala Gln Cys40 45 50 GCG CCT CCG CCC GCC GTG TGC GCG GAG CTG GTG CGC GAG CCG GGC TGC310 Ala Pro Pro Pro Ala Val Cys Ala Glu Leu Val Arg Glu Pro Gly Cys 5560 65 GGC TGC TGC CTG ACG TGC GCA CTG AGC GAG GGC CAG CCG TGC GGC ATC358 Gly Cys Cys Leu Thr Cys Ala Leu Ser Glu Gly Gln Pro Cys Gly Ile 7075 80 TAC ACC GAG CGC TGT GGC TCC GGC CTT CGC TGC CAG CCG TCG CCC GAC406 Tyr Thr Glu Arg Cys Gly Ser Gly Leu Arg Cys Gln Pro Ser Pro Asp 8590 95 GAG GCG CGA CCG CTG CAG GCG CTG CTG GAC GGC CGC GGG CTC TGC GTC454 Glu Ala Arg Pro Leu Gln Ala Leu Leu Asp Gly Arg Gly Leu Cys Val 100105 110 115 AAC GCT AGT GCC GTC AGC CGC CTG CGC GCC TAC CTG CTG CCA GCGCCG 502 Asn Ala Ser Ala Val Ser Arg Leu Arg Ala Tyr Leu Leu Pro Ala Pro120 125 130 CCA GCT CCA GGA AAT GCT AGT GAG TCG GAG GAA GAC CGC AGC GCCGGC 550 Pro Ala Pro Gly Asn Ala Ser Glu Ser Glu Glu Asp Arg Ser Ala Gly135 140 145 AGT GTG GAG AGC CCG TCC GTC TCC AGC ACG CAC CGG GTG TCT GATCCC 598 Ser Val Glu Ser Pro Ser Val Ser Ser Thr His Arg Val Ser Asp Pro150 155 160 AAG TTC CAC CCC CTC CAT TCA AAG ATA ATC ATC ATC AAG AAA GGGCAT 646 Lys Phe His Pro Leu His Ser Lys Ile Ile Ile Ile Lys Lys Gly His165 170 175 GCT AAA GAC AGC CAG CGC TAC AAA GTT GAC TAC GAG TCT CAG AGCACA 694 Ala Lys Asp Ser Gln Arg Tyr Lys Val Asp Tyr Glu Ser Gln Ser Thr180 185 190 195 GAT ACC CAG AAC TTC TCC TCC GAG TCC AAG CGG GAG ACA GAATAT GGT 742 Asp Thr Gln Asn Phe Ser Ser Glu Ser Lys Arg Glu Thr Glu TyrGly 200 205 210 CCC TGC CGT AGA GAA ATG GAA GAC ACA CTG AAT CAC CTG AAGTTC CTC 790 Pro Cys Arg Arg Glu Met Glu Asp Thr Leu Asn His Leu Lys PheLeu 215 220 225 AAT GTG CTG AGT CCC AGG GGT GTA CAC ATT CCC AAC TGT GACAAG AAG 838 Asn Val Leu Ser Pro Arg Gly Val His Ile Pro Asn Cys Asp LysLys 230 235 240 GGA TTT TAT AAG AAA AAG CAG TGT CGC CCT TCC AAA GGC AGGAAG CGG 886 Gly Phe Tyr Lys Lys Lys Gln Cys Arg Pro Ser Lys Gly Arg LysArg 245 250 255 GGC TTC TGC TGG TGT GTG GAT AAG TAT GGG CAG CCT CTC CCAGGC TAC 934 Gly Phe Cys Trp Cys Val Asp Lys Tyr Gly Gln Pro Leu Pro GlyTyr 260 265 270 275 ACC ACC AAG GGG AAG GAG GAC GTG CAC TGC TAC AGC ATGCAG AGC AAG T 983 Thr Thr Lys Gly Lys Glu Asp Val His Cys Tyr Ser MetGln Ser Lys 280 285 290 AGACGCCTGC CGCAAGTTAA TGTGGAGCTC AAATATGCCTTATTTTGCAC AAAAGACTGC 1043 CAAGGACATG ACCAGCAGCT GGCTACAGCC TCGATTTATATTTCTGTTTG TGGTGAACTG 1103 ATTTTTTTTA AACCAAAGTT TAGAAAGAGG TTTTTGAAATGCCTATGGTT TCTTTGAATG 1163 GTAAACTTGA GCATCTTTTC ACTTTCCAGT AGTCAGCAAAGAGCAGTTTG AATTTTCTTG 1223 TCGCTTCCTA TCAAAATATT CAGAGACTCG AGCACAGCACCCAGACTTCA TGCGCCCGTG 1283 GAATGCTCAC CACATGTTGG TCGAAGCGGC CGACCACTGACTTTGTGACT TAGGCGGCTG 1343 TGTTGCCTAT GTAGAGAACA CGCTTCACCC CCACTCCCCGTACAGTGCGC ACAGGCTTTA 1403 TCGAGAATAG GAAAACCTTT AAACCCCGGT CATCCGGACATCCCAACGCA TGCTCCTGGA 1463 GCTCACAGCC TTCTGTGGTG TCATTTCTGA AACAAGGGCGTGGATCCCTC AACCAAGAAG 1523 AATGTTTATG TCTTCAAGTG ACCTGTACTG CTTGGGGACTATTGGAGAAA ATAAGGTGGA 1583 GTCCTACTTG TTTAAAAAAT ATGTATCTAA GAATGTTCTAGGGCACTCTG GGAACCTATA 1643 AAGGCAGGTA TTTCGGGCCC TCCTCTTCAG GAATCTTCCTGAAGACATGG CCCAGTCGAA 1703 GGCCCAGGAT GGCTTTTGCT GCGGCCCCGT GGGGTAGGAGGGACAGAGAG ACGGGAGAGT 1763 CAGCCTCCAC ATTCAGAGGC ATCACAAGTA ATGGCACAATTCTTCGGATG ACTGCAGAAA 1823 ATAGTGTTTT GTAGTTCAAC AACTCAAGAC GAAGCTTATTTCTGAGGATA AGCTCTTTAA 1883 AGGCAAAGCT TTATTTTCAT CTCTCATCTT TTGTCCTCCTTAGCACAATG TAAAAAAGAA 1943 TAGTAATATC AGAACAGGAA GGAGGAATGG CTTGCTGGGGAGCCCATCCA GGACACTGGG 2003 AGCACATAGA GATTCACCCA TGTTTGTTGA ACTTAGAGTCATTCTCATGC TTTTCTTTAT 2063 AATTCACACA TATATGCAGA GAAGATATGT TCTTGTTAACATTGTATACA ACATAGCCCC 2123 AAATATAGTA AGATCTATAC TAGATAATCC TAGATGAAATGTTAGAGATG CTATATGATA 2183 CAACTGTGGC CATGACTGAG GAAAGGAGCT CACGCCCAGAGACTGGGCTG CTCTCCCGGA 2243 GGCCAAACCC AAGAAGGTCT GGCAAAGTCA GGCTCAGGGAGACTCTGCCC TGCTGCAGAC 2303 CTCGGTGTGG ACACACGCTG CATAGAGCTC TCCTTGAAAACAGAGGGGTC TCAAGACATT 2363 CTGCCTACCT ATTAGCTTTT CTTTATTTTT TTAACTTTTTGGGGGGAAAA GTATTTTTGA 2423 GAAGTTTGTC TTGCAATGTA TTTATAAATA GTAAATAAAGTTTTTACCAT T 2474 4989 base pairs nucleic acid single linear cDNA NO NOnot provided A., et al.Ullrich Insulin-like growth factor I receptor...EMBO J. 5 1986 2503-2512 3 TTTTTTTTTT TTTTGAGAAA GGGAATTTCA TCCCAAATAAAAGGAATGAA GTCTGGCTCC 60 GGAGGAGGGT CCCCGACCTC GCTGTGGGGG CTCCTGTTTCTCTCCGCCGC GCTCTCGCTC 120 TGGCCGACGA GTGGAGAAAT CTGCGGGCCA GGCATCGACATCCGCAACGA CTATCAGCAG 180 CTGAAGCGCC TGGAGAACTG CACGGTGATC GAGGGCTACCTCCACATCCT GCTCATCTCC 240 AAGGCCGAGG ACTACCGCAG CTACCGCTTC CCCAAGCTCACGGTCATTAC CGAGTACTTG 300 CTGCTGTTCC GAGTGGCTGG CCTCGAGAGC CTCGGAGACCTCTTCCCCAA CCTCACGGTC 360 ATCCGCGGCT GGAAACTCTT CTACAACTAC GCCCTGGTCATCTTCGAGAT GACCAATCTC 420 AAGGATATTG GGCTTTACAA CCTGAGGAAC ATTACTCGGGGGGCCATCAG GATTGAGAAA 480 AATGCTGACC TCTGTTACCT CTCCACTGTG GACTGGTCCCTGATCCTGGA TGCGGTGTCC 540 AATAACTACA TTGTGGGGAA TAAGCCCCCA AAGGAATGTGGGGACCTGTG TCCAGGGACC 600 ATGGAGGAGA AGCCGATGTG TGAGAAGACC ACCATCAACAATGAGTACAA CTACCGCTGC 660 TGGACCACAA ACCGCTGCCA GAAAATGTGC CCAAGCACGTGTGGGAAGCG GGCGTGCACC 720 GAGAACAATG AGTGCTGCCA CCCCGAGTGC CTGGGCAGCTGCAGCGCGCC TGACAACGAC 780 ACGGCCTGTG TAGCTTGCCG CCACTACTAC TATGCCGGTGTCTGTGTGCC TGCCTGCCCG 840 CCCAACACCT ACAGGTTTGA GGGCTGGCGC TGTGTGGACCGTGACTTCTG CGCCAACATC 900 CTCAGCGCCG AGAGCAGCGA CTCCGAGGGG TTTGTGATCCACGACGGCGA GTGCATGCAG 960 GAGTGCCCCT CGGGCTTCAT CCGCAACGGC AGCCAGAGCATGTACTGCAT CCCTTGTGAA 1020 GGTCCTTGCC CGAAGGTCTG TGAGGAAGAA AAGAAAACAAAGACCATTGA TTCTGTTACT 1080 TCTGCTCAGA TGCTCCAAGG ATGCACCATC TTCAAGGGCAATTTGCTCAT TAACATCCGA 1140 CGGGGGAATA ACATTGCTTC AGAGCTGGAG AACTTCATGGGGCTCATCGA GGTGGTGACG 1200 GGCTACGTGA AGATCCGCCA TTCTCATGCC TTGGTCTCCTTGTCCTTCCT AAAAAACCTT 1260 CGCCTCATCC TAGGAGAGGA GCAGCTAGAA GGGAATTACTCCTTCTACGT CCTCGACAAC 1320 CAGAACTTGC AGCAACTGTG GGACTGGGAC CACCGCAACCTGACCATCAA AGCAGGGAAA 1380 ATGTACTTTG CTTTCAATCC CAAATTATGT GTTTCCGAAATTTACCGCAT GGAGGAAGTG 1440 ACGGGGACTA AAGGGCGCCA AAGCAAAGGG GACATAAACACCAGGAACAA CGGGGAGAGA 1500 GCCTCCTGTG AAAGTGACGT CCTGCATTTC ACCTCCACCACCACGTCGAA GAATCGCATC 1560 ATCATAACCT GGCACCGGTA CCGGCCCCCT GACTACAGGGATCTCATCAG CTTCACCGTT 1620 TACTACAAGG AAGCACCCTT TAAGAATGTC ACAGAGTATGATGGGCAGGA TGCCTGCGGC 1680 TCCAACAGCT GGAACATGGT GGACGTGGAC CTCCCGCCCAACAAGGACGT GGAGCCCGGC 1740 ATCTTACTAC ATGGGCTGAA GCCCTGGACT CAGTACGCCGTTTACGTCAA GGCTGTGACC 1800 CTCACCATGG TGGAGAACGA CCATATCCGT GGGGCCAAGAGTGAGATCTT GTACATTCGC 1860 ACCAATGCTT CAGTTCCTTC CATTCCCTTG GACGTTCTTTCAGCATCGAA CTCCTCTTCT 1920 CAGTTAATCG TGAAGTGGAA CCCTCCCTCT CTGCCCAACGGCAACCTGAG TTACTACATT 1980 GTGCGCTGGC AGCGGCAGCC TCAGGACGGC TACCTTTACCGGCACAATTA CTGCTCCAAA 2040 GACAAAATCC CCATCAGGAA GTATGCCGAC GGCACCATCGACATTGAGGA GGTCACAGAG 2100 AACCCCAAGA CTGAGGTGTG TGGTGGGGAG AAAGGGCCTTGCTGCGCCTG CCCCAAAACT 2160 GAAGCCGAGA AGCAGGCCGA GAAGGAGGAG GCTGAATACCGCAAAGTCTT TGAGAATTTC 2220 CTGCACAACT CCATCTTCGT GCCCAGACCT GAAAGGAAGCGGAGAGATGT CATGCAAGTG 2280 GCCAACACCA CCATGTCCAG CCGAAGCAGG AACACCACGGCCGCAGACAC CTACAACATC 2340 ACCGACCCGG AAGAGCTGGA GACAGAGTAC CCTTTCTTTGAGAGCAGAGT GGATAACAAG 2400 GAGAGAACTG TCATTTCTAA CCTTCGGCCT TTCACATTGTACCGCATCGA TATCCACAGC 2460 TGCAACCACG AGGCTGAGAA GCTGGGCTGC AGCGCCTCCAACTTCGTCTT TGCAAGGACT 2520 ATGCCCGCAG AAGGAGCAGA TGACATTCCT GGGCCAGTGACCTGGGAGCC AAGGCCTGAA 2580 AACTCCATCT TTTTAAAGTG GCCGGAACCT GAGAATCCCAATGGATTGAT TCTAATGTAT 2640 GAAATAAAAT ACGGATCACA AGTTGAGGAT CAGCGAGAATGTGTGTCCAG ACAGGAATAC 2700 AGGAAGTATG GAGGGGCCAA GCTAAACCGG CTAAACCCGGGGAACTACAC AGCCCGGATT 2760 CAGGCCACAT CTCTCTCTGG GAATGGGTCG TGGACAGATCCTGTGTTCTT CTATGTCCAG 2820 GCCAAAACAG GATATGAAAA CTTCATCCAT CTGATCATCGCTCTGCCCGT CGCTGTCCTG 2880 TTGATCGTGG GAGGGTTGGT GATTATGCTG TACGTCTTCCATAGAAAGAG AAATAACAGC 2940 AGGCTGGGGA ATGGAGTGCT GTATGCCTCT GTGAACCCGGAGTACTTCAG CGCTGCTGAT 3000 GTGTACGTTC CTGATGAGTG GGAGGTGGCT CGGGAGAAGATCACCATGAG CCGGGAACTT 3060 GGGCAGGGGT CGTTTGGGAT GGTCTATGAA GGAGTTGCCAAGGGTGTGGT GAAAGATGAA 3120 CCTGAAACCA GAGTGGCCAT TAAAACAGTG AACGAGGCCGCAAGCATGCG TGAGAGGATT 3180 GAGTTTCTCA ACGAAGCTTC TGTGATGAAG GAGTTCAATTGTCACCATGT GGTGCGATTG 3240 CTGGGTGTGG TGTCCCAAGG CCAGCCAACA CTGGTCATCATGGAACTGAT GACACGGGGC 3300 GATCTCAAAA GTTATCTCCG GTCTCTGAGG CCAGAAATGGAGAATAATCC AGTCCTAGCA 3360 CCTCCAAGCC TGAGCAAGAT GATTCAGATG GCCGGAGAGATTGCAGACGG CATGGCATAC 3420 CTCAACGCCA ATAAGTTCGT CCACAGAGAC CTTGCTGCCCGGAATTGCAT GGTAGCCGAA 3480 GATTTCACAG TCAAAATCGG AGATTTTGGT ATGACGCGAGATATCTATGA GACAGACTAT 3540 TACCGGAAAG GAGGCAAAGG GCTGCTGCCC GTGCGCTGGATGTCTCCTGA GTCCCTCAAG 3600 GATGGAGTCT TCACCACTTA CTCGGACGTC TGGTCCTTCGGGGTCGTCCT CTGGGAGATC 3660 GCCACACTGG CCGAGCAGCC CTACCAGGGC TTGTCCAACGAGCAAGTCCT TCGCTTCGTC 3720 ATGGAGGGCG GCCTTCTGGA CAAGCCAGAC AACTGTCCTGACATGCTGTT TGAACTGATG 3780 CGCATGTGCT GGCAGTATAA CCCCAAGATG AGGCCTTCCTTCCTGGAGAT CATCAGCAGC 3840 ATCAAAGAGG AGATGGAGCC TGGCTTCCGG GAGGTCTCCTTCTACTACAG CGAGGAGAAC 3900 AAGCTGCCCG AGCCGGAGGA GCTGGACCTG GAGCCAGAGAACATGGAGAG CGTCCCCCTG 3960 GACCCCTCGG CCTCCTCGTC CTCCCTGCCA CTGCCCGACAGACACTCAGG ACACAAGGCC 4020 GAGAACGGCC CCGGCCCTGG GGTGCTGGTC CTCCGCGCCAGCTTCGACGA GAGACAGCCT 4080 TACGCCCACA TGAACGGGGG CCGCAAGAAC GAGCGGGCCTTGCCGCTGCC CCAGTCTTCG 4140 ACCTGCTGAT CCTTGGATCC TGAATCTGTG CAAACAGTAACGTGTGCGCA CGCGCAGCGG 4200 GGTGGGGGGG GAGAGAGAGT TTTAACAATC CATTCACAAGCCTCCTGTAC CTCAGTGGAT 4260 CTTCAGTTCT GCCCTTGCTG CCCGCGGGAG ACAGCTTCTCTGCAGTAAAA CACATTTGGG 4320 ATGTTCCTTT TTTCAATATG CAAGCAGCTT TTTATTCCCTGCCCAAACCC TTAACTGACA 4380 TGGGCCTTTA AGAACCTTAA TGACAACACT TAATAGCAACAGAGCACTTG AGAACCAGTC 4440 TCCTCACTCT GTCCCTGTCC TTCCCTGTTC TCCCTTTCTCTCTCCTCTCT GCTTCATAAC 4500 GGAAAAATAA TTGCCACAAG TCCAGCTGGG AAGCCCTTTTTATCAGTTTG AGGAAGTGGC 4560 TGTCCCTGTG GCCCCATCCA ACCACTGTAC ACACCCGCCTGACACCGTGG GTCATTACAA 4620 AAAAACACGT GGAGATGGAA ATTTTTACCT TTATCTTTCACCTTTCTAGG GACATGAAAT 4680 TTACAAAGGG CCATCGTTCA TCCAAGGCTG TTACCATTTTAACGCTGCCT AATTTTGCCA 4740 AAATCCTGAA CTTTCTCCCT CATCGGCCCG GCGCTGATTCCTCGTGTCCG GAGGCATGGG 4800 TGAGCATGGC AGCTGGTTGC TCCATTTGAG AGACACGCTGGCGACACACT CCGTCCATCC 4860 GACTGCCCCT GCTGTGCTGC TCAAGGCCAC AGGCACACAGGTCTCATTGC TTCTGACTAG 4920 ATTATTATTT GGGGGAACTG GACACAATAG GTCTTTCTCTCAGTGAAGGT GGGGAGAAGC 4980 TGAACCGGC 4989 25 base pairs nucleic acidsingle linear cDNA NO NO not provided 4 GCGCCCGCTG CATGACGCCT GCAAC 2524 base pairs nucleic acid single linear cDNA NO NO not provided 5CGGGCGGCTC ACCTGGAGCT GGCG 24 18 base pairs nucleic acid single linearcDNA NO NO not provided 6 AGGCGGCTGA CGGCACTA 18 19 base pairs nucleicacid single linear cDNA NO NO not provided 7 CAGGCGTCAT GCAGCGGGC 19 25base pairs nucleic acid single linear cDNA NO NO not provided 8CGGAGATGCC GCATGCCAGC GCAGG 25 18 base pairs nucleic acid single linearcDNA NO NO not provided 9 GACAGCGTCG GAGCGATC 18 18 base pairs nucleicacid single linear cDNA NO NO not provided 10 ATCTCTCCGC TTCCTTTC 18 18base pairs nucleic acid single linear cDNA NO NO not provided 11GAAAGGAAGC GGAGAGAT 18

What is claimed is:
 1. A nucleic acid molecule comprising at least about10 nucleotides that hybridizes to or forms a heteroduplex with an mRNAmolecule directed from a gene corresponding to a genomic form of SEQ IDNO:1 or SEQ ID NO:2 and which thereby reduces translation of said mRNAmolecule.
 2. A nucleic molecule according to claim 1 wherein saidmolecule comprises at least about 15 nucleotides.
 3. A nucleic acidmolecule according to claim 2 wherein said molecule hybridizes to orforms a heteroduplex with at least one nucleotide sequence of about 15nucleotides in length present as a contiguous sequence within SEQ IDNO:1 or SEQ. ID NO:2.
 4. A ribozyme comprising a hybridising region anda catalytic region wherein the hybridising region is capable ofhybridising to at least part of a target mRNA sequence transcribed froma genomic gene corresponding to SEQ ID NO:1 or SEQ ID NO:2 wherein saidcatalytic domain is capable of cleaving said target mRNA sequence toreduce or inhibit IGF-I mediated cell proliferation or inflammation. 5.A pharmaceutical composition for topical administration said compositioncomprising a nucleic acid molecule that inhibits or otherwise reducesIGF-1 mediated cell proliferation wherein said nucleic acid comprises atleast about ten nucleotides and hybridizes to or forms a heteroduplexwith an mRNA molecule directed from a gene encoding human IGFBP-2 orIGFBP-3, said composition further comprising one or morepharmaceutically acceptable carriers.
 6. A pharmaceutical compositionaccording to claim 5 wherein said antisense molecule hybridizes to orforms a duplex with at least one nucleotide sequence of about 15nucleotides in length present as a contiguous sequence within SEQ IDNO:2.